8-K

UNITED STATES

SECURITIES AND EXCHANGE COMMISSION

Washington, D.C. 20549

FORM 8-K

CURRENT REPORT

Pursuant to Section 13 or 15(d)

of the Securities Exchange Act of 1934

Date of Report (Date of earliest event reported): September 21, 2016

MYOKARDIA, INC.

(Exact name of registrant as specified in its charter)

Delaware	001-37609	44-5500552
(State or other jurisdiction of incorporation)	(Commission File Number)	(I.R.S. Employer Identification No.)

333 Allerton Ave.

South San Francisco, CA 94080

(Address of principal executive offices, including zip code)

(650) 741-0900

(Registrant’s telephone number, including area code)

Not Applicable

(Former Name or Former Address, if Changed Since Last Report)

Check the appropriate box below if the Form 8-K filing is intended to simultaneously satisfy the filing obligation of the registrant under any of the following provisions:

¨ Written communications pursuant to Rule 425 under the Securities Act (17 CFR 230.425)

¨ Soliciting material pursuant to Rule 14a-12 under the Exchange Act (17 CFR 240.14a-12)

¨ Pre-commencement communications pursuant to Rule 14d-2(b) under the Exchange Act (17 CFR 240.14d-2(b))

¨ Pre-commencement communications pursuant to Rule 13e-4(c) under the Exchange Act (17 CFR 240.13e-4(c))

Item 7.01 Regulation FD Disclosure

On September 21, 2016, MyoKardia, Inc., a Delaware corporation (the “Company”), issued a press release titled, “MyoKardia Outlines Path to Registration for MYK-461 in Symptomatic, Obstructive Hypertrophic Cardiomyopathy Patients and Provides Pipeline and Research Updates at Inaugural R&D Day” (the “Press Release”). The Press Release is furnished herewith as Exhibit 99.1.

On September 21, 2016, the Company intends to deliver a corporate presentation at its Research and Development (R&D) Day for analysts and investors at 8:30 a.m. EST, during which the Company will present certain slides (the “Presentation”). A copy of the Presentation is furnished herewith as Exhibit 99.2 to this Current Report on Form 8-K.

The information in this Item 7.01 and Exhibits 99.1 and 99.2 attached hereto is intended to be furnished and shall not be deemed “filed” for purposes of Section 18 of the Securities Exchange Act of 1934, as amended (the “Exchange Act”), or otherwise subject to the liabilities of that section, nor shall it be deemed incorporated by reference in any filing under the Securities Act of 1933, as amended, or the Exchange Act, except as expressly set forth by specific reference in such filing.

The furnishing of the Presentation is not an admission as to the materiality of any information therein. The information contained in the slide is summary information that is intended to be considered in the context of more complete information included in the Company’s filings with the Securities and Exchange Commission (the “SEC”) and other public announcements that the Company has made and may make from time to time by press release or otherwise. The Company undertakes no duty or obligation to update or revise the information contained in this report, although it may do so from time to time as its management believes is appropriate. Any such updating may be made through the filing of other reports or documents with the SEC, through press releases or through other public disclosures.

Item 9.01 Financial Statements and Exhibits

(d) Exhibits.

Exhibit No.	Description
99.1	Press Release dated September 21, 2016, furnished herewith
99.2	September 21, 2016 Company presentation: R&D Day, furnished herewith

SIGNATURES

Pursuant to the requirements of the Securities Exchange Act of 1934, the registrant has duly caused this report to be signed on its behalf by the undersigned hereunto duly authorized.

Date: September 21, 2016	MyoKardia, Inc.
	By:	/s/ Jake Bauer
		Jake Bauer
		Senior Vice President, Finance & Corporate Development (principal financial officer)

EXHIBIT INDEX

Exhibit No.	Description
99.1	Press Release dated September 21, 2016, furnished herewith
99.2	September 21, 2016 Company presentation: R&D Day, furnished herewith

EX-99.1

Exhibit 99.1

MyoKardia Outlines Path to Registration for MYK-461 in Symptomatic,

Obstructive Hypertrophic Cardiomyopathy Patients and Provides Pipeline and

Research Updates at Inaugural R&D Day

Phase 2 PIONEER-HCM Pilot Study of MYK-461 Under Way with Topline Data Expected in

Second Half of 2017

Mortality-Based Efficacy Endpoints Not Required for Registration of MYK-461 Obstructive

Hypertrophic Cardiomyopathy (oHCM) Program

Phase 1 Program for MYK-491 for Dilated Cardiomyopathy (DCM) Expected to Initiate in

First Half of 2017

SOUTH SAN FRANCISCO, Calif. – September 21, 2016 – MyoKardia, Inc. (Nasdaq: MYOK), a clinical stage biopharmaceutical company pioneering a precision medicine approach for the treatment of heritable cardiovascular diseases, will highlight today the expected path to registration for its lead product candidate MYK-461 in the initial indication of symptomatic oHCM and its plans to progress MYK-491 into the clinic for DCM. The Company’s scientific leadership will also provide further insights into MyoKardia’s precision medicine and pipeline strategy enabled by its product engine. The updates will be presented at MyoKardia’s inaugural R&D Day today in New York.

“We believe our precision medicine strategy and strong scientific foundation will continue to drive novel therapies aimed at addressing important treatment needs for patients with serious cardiovascular diseases,” said Tassos Gianakakos, chief executive officer. “The encouraging early results from our two most advanced programs have supported our enthusiastic advancement of both into the next stage of development.”

“Our recent discussions with the U.S. Food and Drug Administration (FDA), including confirmation that mortality-based efficacy endpoints will not be required for registration, represent an important milestone for MyoKardia, allowing us to confirm MyoKardia’s plans for registration of MYK-461 in oHCM.”

Mr. Gianakakos continued, “We are also excited to share more detail around our MYK-491 clinical program for the treatment of DCM. MYK-491 is the second clinical candidate generated by MyoKardia’s product engine and has shown promising preclinical data that supplies us with a compelling rationale to support advancement into Phase 1 in the first half of next year in a disease area desperate for more therapeutic options.”

MYK-461 in oHCM

Conclusions from Recent Regulatory Interactions

Additionally, MyoKardia will report key conclusions from recent regulatory interactions, which clarify the potential clinical development pathway in oHCM:

• Mortality-based efficacy endpoints will not be required for registration.

• Improvement in functional capacity and/or clinical symptoms are suitable endpoints for registration.

• A single Phase 3 pivotal study demonstrating significant improvement in functional capacity or symptoms may be adequate for approval.

Further Detail on PIONEER-HCM

MyoKardia has initiated a Phase 2 study, PIONEER-HCM, which is an open-label, single-arm pilot study of MYK-461 in patients with symptomatic oHCM, an indication for which the FDA granted MYK-461 Orphan Drug Designation in 2016. Other details include:

• First outpatient study with MYK-461 in target indicated population for anticipated treatment duration.

• Primary endpoint is to assess level of reduction in left ventricular outflow tract (LVOT) gradient over 12 weeks of drug exposure.

• Based on published studies and MyoKardia research, LVOT gradient reduction is expected to improve symptoms and functional capacity.

• PIONEER-HCM will begin to characterize relationships among reductions in contractility, LVOT gradient and endpoints including functional capacity and clinical symptoms.

• Topline data is expected to be released in the second half of 2017.

• Study is designed to enable progression to larger Phase 2 study to finalize dosing and endpoints before subsequent single pivotal study.

Phase 1 Data

Duke University School of Medicine Professor Andrew Wang, M.D., a participant in the MYK-461 investigational program, will review Phase 1 data in detail, including additional information around the two patients with LVOT obstruction dosed in the Company’s Phase 1 single ascending dose (SAD) study in HCM patients and additional pharmacokinetic, or PK, and pharmacodynamic, or PD, data from the SAD and multiple ascending dose (MAD) studies of MYK-461.

MYK-491 in DCM

MYK-491 is the Company’s candidate for several well-defined sub-groups of DCM, including genetic DCM, designed to return the diseased DCM heart to normal contractility by increasing the overall force of the heart’s contraction. Similar to MYK-461, MYK-491 targets the underlying biomechanical defect caused by sarcomere mutations and has been designed to be potentially disease modifying.

Other updates on the MYK-491 program include:

• Preclinical research demonstrates across multiple animal model systems that MYK-491 is able to achieve significant, dose-dependent increases in stroke volume with minimal effect on diastolic function.

• MyoKardia intends to initiate a Phase 1 SAD study in the first half of 2017, with topline results expected in the third quarter of 2017.

Precision Medicine Platform and Vision 2020

During the R&D Day presentations, MyoKardia leadership will also discuss key elements of the Company’s strategy, including its precision medicine approach and product engine and future objectives for its research activities.

“We are working hard at MyoKardia to build a company that represents much more than two product candidates. The efficiency with which these drugs have moved into and through clinical trials and their promising early results are a testament to our team and to our precision approach. Through the dedication of our employees, the commitment of our founders and the cardiomyopathy community’s support, in just four years we have built a durable competitive advantage in our field, which forms the basis for our Vision 2020 strategy,” said Mr. Gianakakos.

“We look forward to sharing more details on how we hope to fulfill our mission to change the world for patients with serious cardiovascular disease through bold and innovative science.”

In addition to Mr. Gianakakos and Dr. Wang, R&D Day presenters include:

• Jonathan Fox, M.D., Ph.D., chief medical officer; Michael Graziano, Ph.D., vice president, research biology; Robert McDowell, Ph.D., senior vice president, drug discovery

• Christine Seidman, M.D., a MyoKardia co-founder and professor of genetics and the Thomas W. Smith professor of medicine at Harvard Medical School and Brigham and Women’s Hospital

• Srihari Naidu, M.D., director, Cardiac Catheterization Laboratory, Interventional Cardiology Fellowship Program and HCM Treatment Center at Winthrop University Hospital

• Daniel Judge, M.D., associate professor of medicine, Johns Hopkins University School of Medicine; Medical Director, Center for Inherited Heart Disease

R&D Day Webcast

To access the live webcast of MyoKardia’s R&D Day presentation, please visit the “Events & Presentations” page within the Investors & Media section of the MyoKardia website at http://investors.myokardia.com. A replay of the webcast will be available on the MyoKardia website for 30 days following the event.

About MYK-461 and PIONEER-HCM

MYK-461 is an orally administered small molecule designed to reduce left ventricular contractility by allosterically modulating the function of cardiac myosin, the motor protein driving heart muscle contraction. MyoKardia has evaluated MYK-461 in three Phase 1 clinical trials, which have been primarily designed to evaluate safety and tolerability of oral doses of MYK-461 and are providing data on its pharmacokinetic and pharmacodynamic profile. These studies assess MYK-461’s engagement of cardiac myosin by measuring reduction in cardiac muscle contractility via several independent echocardiographic measurements. In April 2016, the U.S. FDA granted the company Orphan Drug Designation for MYK-461 for treatment of symptomatic oHCM, a subset of HCM. MyoKardia is currently enrolling patients for PIONEER-HCM, a Phase 2 open-label pilot study to evaluate safety and efficacy of MYK-461 in subjects with symptomatic oHCM.

About HCM and oHCM

It is estimated that one in every 500 people in the United States has HCM, the most prevalent form of heritable cardiomyopathy. HCM is defined as an otherwise unexplained thickening of the walls of the heart, known as hypertrophy. The consequences include reduced left ventricular volumes and cardiac output, reduced ability of the left ventricle to expand, and elevated filling pressures. These can all contribute to reduced effort tolerance and symptoms that include shortness of breath and chest pain. HCM is a chronic disease and for the majority of patients, the disease progresses slowly and can be extremely disabling. HCM substantially increases the risk of developing atrial fibrillation that can lead to stroke or malignant ventricular arrhythmias that can cause sudden cardiac death. There are currently no approved drug products indicated for the treatment of HCM. Patients are typically prescribed one or more drugs (including beta blockers, non-dihydropyridine calcium channel blockers and disopyramide) indicated for the treatment of hypertension, heart failure or other cardiovascular disorders more generally.

Approximately two thirds of all HCM patients have obstruction, either at rest or with provocation like exercise. oHCM is a physiological complication of HCM in which the thickened heart muscle obstructs the left ventricular outflow tract (LVOT). Measured most commonly by non-invasive imaging (echocardiography), oHCM is defined as ³30 mm Hg pressure gradient across the LVOT. Symptoms of oHCM can include shortness of breath, chest pain, dizziness, fainting, and palpitations. The presence of obstruction in an HCM patient further increases risk of progression to severe symptoms, and risk of death from heart failure or stroke.

The degree of LVOT obstruction in oHCM patients is a primary criterion for surgical and other invasive interventions (recommended for symptomatic patients with LVOT gradients measured at ³50 mmHg). Relief of obstruction has been associated with improved symptoms, function and clinical outcomes. Surgical or other invasive interventions, including septal myectomy, an open heart procedure, may be appropriate. There are no approved drug products indicated for this condition. MyoKardia plans to explore obstruction relief as measured by LVOT gradient reduction as a primary endpoint in the Phase 2 PIONEER-HCM pilot study.

About MyoKardia

MyoKardia is a clinical stage biopharmaceutical company pioneering a precision medicine approach to discover, develop and commercialize targeted therapies for the treatment of serious and rare cardiovascular diseases. MyoKardia’s initial focus is on the treatment of heritable cardiomyopathies, a group of rare, genetically-driven forms of heart failure that result from biomechanical defects in cardiac muscle contraction. MyoKardia has used its precision medicine platform to generate a pipeline of therapeutic programs for the chronic treatment of the two most prevalent forms of heritable cardiomyopathy—hypertrophic cardiomyopathy, or HCM, and dilated cardiomyopathy, or DCM. MyoKardia’s most advanced product candidate, MYK-461, is an orally-administered small molecule designed to reduce excessive cardiac muscle contractility leading to HCM and has been evaluated in three Phase 1 clinical trials. MyoKardia is now studying MYK-461 in a Phase 2 PIONEER-HCM pilot study in symptomatic oHCM, for which the FDA has granted MYK-461 Orphan Drug Designation. A cornerstone of the MyoKardia platform is the Sarcomeric Human Cardiomyopathy Registry, or SHaRe, a multi-center, international repository of clinical and laboratory data on individuals and families with genetic heart disease, which MyoKardia helped form in 2014. MyoKardia believes that SHaRe, currently consisting of data from approximately 10,000 individuals, is the world’s largest registry of patients with heritable cardiomyopathies. MyoKardia’s purpose is to improve the lives of patients and families suffering from cardiovascular disease by creating targeted therapies that can change the course of their condition. For more information, please visit www.myokardia.com.

Forward-Looking Statements

Statements we make in this press release may include statements which are not historical facts and are considered forward-looking within the meaning of Section 27A of the Securities Act of 1933, as amended, and Section 21E of the Securities Exchange Act of 1934, as amended, which are usually identified by the use of words such as “anticipates,” “believes,” “estimates,” “expects,” “intends,” “may,” “plans,” “projects,” “seeks,” “should,” “will,” and variations of such words or similar expressions. We intend these forward-looking statements to be covered by the safe harbor provisions for forward-looking statements contained in Section 27A of the Securities Act and Section 21E of the Securities Exchange Act and are making this statement for purposes of complying with those safe harbor provisions. These forward-looking statements, including statements regarding the clinical and therapeutic potential of MYK-461 and MYK-491, the Company’s ability to generate topline data from its Phase 2 PIONEER-HCM study, the Company’s ability to advance MYK-491 into a Phase 1 clinical trial for DCM and generate topline data from this trial, the timing of these events, and the anticipated clinical endpoints and pathway to approval for MYK-461, reflect our current views about our plans, intentions, expectations, strategies and prospects, which are based on the information currently available to us and on assumptions we have made. Although we believe that our plans, intentions, expectations, strategies and prospects as reflected in or suggested by those forward-looking statements are reasonable, we can give no assurance that the plans, intentions, expectations or strategies will be attained or achieved. Furthermore, actual results may differ materially from those described in the forward-looking

statements and will be affected by a variety of risks and factors that are beyond our control including, without limitation, risks associated with the development and regulation of our product candidates, as well as those set forth in our Annual Report on Form 10-K for the fiscal year ended December 31, 2015, our Quarterly Report on Form 10-Q for the quarter ended June 30, 2016, our Registration Statement on Form S-1 (File No. 333-213680) filed with the Securities and Exchange Commission (SEC) on September 16, 2016 and our other filings with the SEC. Except as required by law, we assume no obligation to update publicly any forward-looking statements, whether as a result of new information, future events or otherwise.

Investor Contact:

Beth DelGiacco

Stern Investor Relations, Inc.

212-362-1200

beth@sternir.com

Media Contact:

Steven Cooper

Edelman

415-486-3264

steven.cooper@edelman.com

EX-99.2

Exhibit 99.2

Exhibit 99.2

Welcome to R&D Day

Vision 2020

September 21, 2016

Safe-Harbor and Forward Looking Statements

Statements in this presentation may include statements which are not historical facts and are considered forward-looking within the meaning of Section 27A of the Securities Act of 1933 and Section 21E of the Securities Exchange Act of 1934, which are usually identified by the use of words such as “anticipates,” “believes,” “estimates,” “expects,” “intends,” “may,” “plans,” “projects,” “seeks,” “should,” “will,” and variations of such words or similar expressions. We intend these forward-looking statements to be covered by the safe harbor provisions for forward-looking statements contained in Section 27A of the Securities Act and Section 21E of the Securities Exchange Act and are making this statement for purposes of complying with those safe harbor provisions. These forward-looking statements, including statements regarding the clinical and therapeutic potential of MYK-461, MYK-491 and other product candidates that we may identify from our pipeline, our ability to generate topline data from our PIONEER-HCM trial and additional data from our Phase 1 MAD trial of MYK-461, our ability to initiate a Phase 1 clinical trial of MYK-491 in DCM, the timing of such events, the potential endpoints for our PIONEER-HCM trial and further clinical trials of our product candidates, and our ability to maintain, and to receive funding from, our collaboration with Sanofi, reflect our current views about our plans, intentions, expectations, strategies and prospects, which are based on the information currently available to us and on assumptions we have made.

Although we believe that our plans, intentions, expectations, strategies and prospects as reflected in or suggested by those forward-looking statements are reasonable, we can give no assurance that the plans, intentions, expectations or strategies will be attained or achieved. Furthermore, actual results may differ materially from those described in the forward-looking statements and will be affected by a variety of risks and factors that are beyond our control including, without limitation, risks associated with our precision medicine platform and the discovery, development and regulation of our product candidates and risks associated with our reliance on third parties, as well as those set forth in our Annual Report on Form 10-K for the fiscal year ended December 31, 2015, our Quarterly Report on Form 10-Q for the quarter ended June 30, 2016, our Registration Statement on Form S-1 (File No. 333-213680) filed with the SEC on September 16, 2016 and our other filings with the SEC. Except as required by law, we assume no obligation to update publicly any forward-looking statements, whether as a result of new information, future events or otherwise.

2

Welcome and Vision 2020

Tassos Gianakakos Chief Executive Officer

Goals for Today

1. Provide perspective from HCM and DCM and thought leaders

2. Outline MYK-461’s path to registration informed by regulatory interactions

• Mortality-based efficacy endpoints will not be required for registration

• Improvement in functional capacity and/or clinical symptoms are suitable endpoints for registration

• A single Phase 3 pivotal study demonstrating significant improvement in functional capacity or symptoms may be adequate for approval

3. Introduce MYK-491; advancing into Phase 1 studies for DCM

4. Dive deeper into how MyoKardia’s precision medicine product engine creates novel therapies aimed at important disease areas

5. Provide visibility to multiple data catalysts on the horizon throughout 2017

4

Rethinking Cardiovascular Disease

Our Mission: to change the world for patients with serious cardiovascular disease through bold and innovative science

5

Key Elements of Our Precision Medicine Strategy and Product Engine

Mechanistic understanding of underlying drivers of disease

Therapies to directly modulate targets in causal pathway

Highly predictive assays and model systems

Efficient registration path with early proof-of-concept

Continuous feedback loop to develop best-in-class solutions

6

Application of MyoKardia Precision Medicine Strategy Has Led to Clinical Proof of Concept in Our Lead Program

Underlying Etiology Precision Medicine

• Genetics

• Ischemic Selection of disease targets in

• Acute or other causes

causal pathway; informed by scientific depth Identification of patient populations most likely to benefit

MYK-461 MYK-491

Clinical Features

Mechanism of Action

• Non-invasive imaging

• Target underlying cause

• Symptom, function

• Enhance / reduce power output

• Stage of disease

• Future programs

• Co-morbidities

• Efficiently achieve first-in-class; POC: target well-defined patient populations MyoKardia with clear mechanistic rationale

Implications

• Quickly validate mechanistic hypothesis through efficient clinical trial design

7

Product Engine Expected to Produce Future Novel Therapies and Significant Improvement for Patients

Our Aspirations:

• Leadership position in our therapeutic area(s) • Best-in-class offerings

• Potential for disease

Continual    feedback loop; modification virtuous cycle Registration based on function and symptoms

Efficiently achieve POC in targeted population(s)

8

Vision 2020: Key Elements Defining Success

1

Successfully launch MYK-461 in the United States

2

Build a rich, differentiated pipeline of product candidates targeted to heritable cardiovascular disease, with two additional programs in development

3

Be recognized as the world’s leader in the science and treatment of heritable cardiomyopathies

4

Attract, empower and inspire the right people

9

MyoKardia’s Current Disease Targets Informed by Underlying

Biomechanical Defect

Hypertrophic cardiomyopathy Dilated cardiomyopathy Normal heart (HCM) (DCM)

Normal Excessive Impaired Inadequate contraction contraction relaxation contraction

10

Large Affected Patient Population Segmented into Rare Disease Subgroups

Total U.S. heart failure population of ~6 million

Hypertrophic Cardiomyopathy Idiopathic Dilated Cardiomyopathy

(630,000) (900,000)

Obstructive HCM Non-obstructive Genetic DCM Idiopathic DCM with unknown

(410,000) HCM (220,000) (gDCM) (360,000) genetic cause(1)

Initial MYK-461 461 Initial

-

Target: nHCM MYK-491

Symptomatic Patient Patient Target: Patient Patient

MYK     oHCM (Orphan Other Segments Other Segments Specific Other Segments Other Segments

Drug Designation) Future Target: subgroup(s)

NOTE: All figures approximate. Abbreviations used: Hypertrophic cardiomyopathy = HCM; Dilated cardiomyopathy = DCM; Obstructive HCM = oHCM.

(1) Represents approximately 60% of idiopathic DCM. Consists of “phenotype positive / genotype negative” patients as well as patients with genetic variants of currently unknown significance.

11

Our Two Lead Product Candidates to Treat HCM and DCM

MYK-461 MYK-491

• Hypertrophic Cardiomyopathy

• Dilated Cardiomyopathy (DCM) (HCM) Disease • Initial Indication: specific, well-

• Initial Indication: symptomatic,

Indication defined sub-segments of DCM obstructive HCM (oHCM) (i.e., genetic DCM)

Orphan Drug Designation

• First drug to target an underlying • First drug to target an underlying Drug Profile cause of HCM cause of DCM

• Oral small molecule • Oral small molecule

Therapeutic • Allosteric inhibitor of myosin • Allosteric activator of myosin

• Reduce power output (contractility) • Increase power output

Hypothesis

• Inhibit formation of actin-myosin • Promote formation of actin-myosin and MOA crossbridges crossbridges

• Phase 2 trial (PIONEER-HCM)

Status • Initiate Phase 1 trial in H1 2017 ongoing; topline data H2 2017

12

Pipeline of First-in-Class Targeted Therapies

U.S. Ex-U.S. Program Discovery Preclinical Phase 1 Phase 2 rights rights

MYK-461:

Symptomatic, obstructive HCM (Orphan Designation)

MYK-461:

Non-Obstructive HCM

MYK-491:

Genetic DCM

HCM-2:

Additional HCM subtype

LUS-1:

RCM, additional HCM, DCM subtypes

Current Stage MyoKardia

Anticipated Development Path through 2017 Sanofi

13

MyoKardia R&D Day Agenda

Welcome and Vision 2020

Tassos Gianakakos

Chief Executive Officer

MyoKardia’s Scientific Foundation

Christine Seidman, M.D.

Co-Founder, MyoKardia

Professor of Genetics and the Thomas W. Smith Professor of Medicine Harvard Medical School and Brigham and Women’s Hospital

An Overview of Hypertrophic Cardiomyopathy

Srihari Naidu, M.D.

Director, Cardiac Catheterization Laboratory, Interventional Cardiology Fellowship Program and HCM Treatment Center at Winthrop University Hospital

HCM Clinician Roundtable and Q&A

Srihari Naidu, M.D.; Christine Seidman, M.D; Andrew Wang, M.D.

MYK-461 Phase 1 Studies in Hypertrophic Cardiomyopathy

Andrew Wang, M.D.

Professor, Duke University School of Medicine

MYK-461 and the Path to Registration

Jonathan Fox, M.D., Ph.D.

Chief Medical Officer

14

MyoKardia R&D Day Agenda (cont’d)

Q&A Followed by Break

An Overview of Dilated Cardiomyopathy

Daniel Judge, M.D.

Associate Professor of Medicine, Johns Hopkins University School of Medicine; Medical Director, Center for Inherited Heart Disease

MyoKardia’s DCM Program: MYK-491

Robert McDowell, Ph.D.

Senior Vice President, Drug Discovery

Research Directions Toward Vision 2020

Michael Graziano, Ph.D.

Vice President, Research Biology

Closing Remarks and Q&A

15

MyoKardia’s Scientific Foundation

Christine Seidman, M.D. Co-Founder, MyoKardia

Professor of Genetics and the Thomas W. Smith Professor of Medicine

Harvard Medical School and Brigham and Women’s Hospital

MyoKardia Progress Builds Upon Decades of Work

Vol. 328, 536-539 August 1987

Myosin subfragment-1 is sufficient to move actin filaments in vitro

Yoko Yano Toyoshima, Stephen J. Krom,

Elizabeth M. McNally*, Kenneth R. Niebling,

Chikashi Toyoshima & James A. spudich

Coexpression and assembly of myosin heavy chain and myosin light chain in Escherichia coli

Elizabeth M. McNally*, Elizabeth B. Goodwin†, James A. Spudich‡, and Leslie A. Leinwand*§

A Molecular Basis for Familial Hypertrophic Cardiomyopathy: A ß Cardiac Myosin Heavy Chain Gene Missense Mutation

Anja A. T. Geisterfer-Lowrance,* Susan Kass, †

Gary Tanigawa,† Hans-Peter Vosberg, ‡

William McKenna,§ Christine E. Seidman,*

and J. G. Seidman†

Vol. 85, pp. 7270-7273, October 1988

Vol. 62, 999-1006, September 1990

17

Cardiac Muscle Disruptions Caused by Defective Contractile Proteins

Heart Muscle Fibers Myofibril

Normal Sarcomere

Actin thin filament Actin-myosin cross-bridge

Myosin thick filament

Force-producing myosin head

18

Deep Understanding of How Changes in Cardiac Muscle Biology Impact Normal Heart Function

Cardiac Sarcomere Components

Myosin binding protein C

Troponin T Troponin I

á Tropomyosin

Actin

Myosin light  Myosin chain heavy chain

Mutations in any of the structural and regulatory components of the sarcomere…

Chemomechanical Cycle

ATP

ADP

-Pi

…impact the chemomechanical cycle and how well the heart functions

19

MyoKardia’s Product Candidates are Designed to Correct the

Underlying Causal Defects

Normal Sarcomere

HCM Sarcomere DCM Sarcomere

Too many engaged Inadequate engaged cross-bridges cross-bridges

20

Cardiomyopathies Result from Three Distinct Types of Cardiac Muscle Disruptions

Hypertrophic Cardiomyopathy Dilated Cardiomyopathy Normal Heart (HCM) (DCM)

Normal Excessive Impaired Inadequate contraction contraction relaxation contraction

21

MyoKardia Has Created the World’s Leading Cardiomyopathy Registry

The Sarcomeric Human

Cardiomyopathy Registry (SHaRe) supports:

• Research (target discovery, etc.)

• Clinical development and registration

• Patient-caregiver community connectivity

World-class academic 11 centers, 10,000+ patients Novel genetic and collaborators …and growing clinical insights

22

Initial Examples of How We Intend to Leverage SHaRe to Augment Corporate Capabilities

Natural History Comprehensive picture of disease natural history of Disease • Define unmet needs

• Identify subpopulations to study

Role of Understand the role of genetic mutations in the natural history Mutations of disease

Advancing hypotheses that Mechanistic define MyoKardia next-generation programs

Hypotheses • Identify subdomains of proteins implicated by genetics as potential therapeutic targets

23

WINTHROP

Institute for Heart Care

An Overview of Hypertrophic Cardiomyopathy

Srihari S. Naidu, MD, FACC, FAHA, FSCAI

Director, Cardiac Catheterization Laboratory and Hypertrophic Cardiomyopathy, Winthrop University Hospital, Associate Professor of Medicine, SUNY – Stony Brook School of Medicine ; Past Trustee, SCAI ; Trustee, Brown University

Hypertrophic Cardiomyopathy

“Quick Facts”

WINTHROP

Institute for Heart Care

1. Most common genetic cardiovascular disease

2. Described first in 1957 by pathologist Donald Teare

3. Prevalence of phenotypically expressed HCM in the adult population ~0.2% (1:500; affects ~630,000 people in the US)

4. Most patients identified in their 30s to 50s

5. Both obstructive (oHCM) and non-obstructive (nHCM)

• ~1/3 with a resting gradient

• ~1/3 with a provocable gradient

• ~1/3 are non-obstructive

6. #1 cause of SCD in young athletes

• Majority suffer from heart failure symptoms

7. Common cause of heart failure, syncope, arrhythmias, palpitations as patients age

25

High Public Awareness of SCD, but Poor Understanding of Predominant

WINTHROP

Institute for Heart Care Burden of Disease

• HCM is the #1 cause of SCD in the United States

• For the vast majority of patients, HCM is slow, debilitating heart failure

– High burden of disease

– Shortness of breath, chest pain, palpitations or dizziness

– SCD is just the tip of the iceberg in HCM!

Oklahoma State Linebacker Mabin Retires From Football due to HCM

August 30, 2016

26

Alcohol Septal Ablation:

My Entry into the World of HCM

Currently manage >800 HCM patients in my care

28

American Heart Association WINTHROP Guidelines & International Textbook

Institute for Heart Care

Expanded 2nd Edition in Production 2018 Expected Press Date

29

Echocardiography

WINTHROP

Institute for Heart Care

30

LVOT Obstruction

WINTHROP

Institute for Heart Care

31

Continuous Doppler

WINTHROP

Institute for Heart Care

(Ray B and Martinez M, in Naidu, S., Ed. Hypertrophic Cardiomyopathy, 2015)

LVOT Obstruction Increases Risk of Severe Heart Failure or

WINTHROP

Institute for Heart Care Death from HF or Stroke

J Am Coll Cardiol 2005;46:470-6.

33

Reduction in LVOT Obstruction Improves Symptoms

WINTHROP

Institute for Heart Care

Surgical Myectomy Septal Ablation

Circulation. 1996;94:467-71. Circulation. 2008;118:131-139.

34

Pharmacologic Treatment of WINTHROP LVOT Obstruction

Institute for Heart Care

2011 ACC/AHA HCM GUIDELINES

• Beta-blocking drugs are recommended (Class I) for the treatment of symptoms (angina or dyspnea) in adult patients with obstructive or nonobstructive HCM

• Verapamil therapy is recommended (Class I) for refractory patients with obstructive or nonobstructive HCM who do not respond to beta-blocking drugs. However, verapamil should be used with caution in patients with high gradients, advanced heart failure, or sinus bradycardia

• Disopyramide is recommended (Class IIa) but fraught with problems:

– Proarrhythmia, necessitating monitoring

– Significant side effects, impacting QoL

– Variable efficacy

J Am Coll Cardiol 2011;58:e212– 60.

35

Mechanism of Action of Therapies WINTHROP to Relieve Obstruction

Institute for Heart Care

Obstruction

Symptoms

oHCM

Thickening

36

The Need for an Alternative

WINTHROP

Institute for Heart Care

• Invasive therapies

– Death in 0.5-1%

– VSD, aortic valve injury in 1-2%

– PPM implantation in 3-8%

– Risk of arrhythmias

– Recuperation time and days off from work

– Technically demanding

– Not available to all patients (< 3,500 total)

37

Key Takeaways

WINTHROP

Institute for Heart Care

• Most common genetic cardiovascular disease

• Common cause of heart failure, syncope, arrhythmias, palpitations as patients age

• Current medication options for HCM are used off-label and have significant side effects: beta blockers, non-dihydropyridine calcium channel blockers and disopyramide

• LVOT obstruction increases risk of severe HF or death

• Relief of obstruction improves symptoms and function

• Surgical treatment options are invasive, have associated risk of complications, are technically demanding and not available to all

• Dedicated medications for underlying biomechanical cause of HCM is an unmet need

38

HCM Clinician Roundtable and Q&A

MYK-461 Phase 1 Studies in

Hypertrophic Cardiomyopathy

Andrew Wang, MD, FACC, FAHA Professor of Medicine

Director, Hypertrophic Cardiomyopathy Clinic

Program Director, Cardiovascular Disease Fellowship

My Experience Treating HCM in Practice at Duke

Adult Cardiovascular Genetics: Dedicated HCM clinic and physicians, genetic counselor

Referral center for management of oHCM, including surgical myectomy, alcohol septal ablation; and EP, advanced heart failure therapies

Limitations of guideline-based treatment—an opportunity for a better therapy

HCM Treatment Algorithm

DukeMedicine

HCM Clinic

General

Cardiologist

HCM

Specialist

Surgeon

Mild or moderate symptoms

Persistent symptoms

Refractory or severe symptoms

LOVT Obstraction

Surgical myectomy Alcohol ablation

Non-obstractive

Transplant

Beta blocker Verapamil

Beta blocker Verapamil

42

Three Phase 1 Trials of MYK-461 in HCM Patients and Healthy Volunteers

MYK-461-001 MYK-461-002 MYK-461-003

Single Ascending Dose (SAD) Multiple Ascending Dose (MAD) SAD Trial in Healthy Volunteers Trial in HCM Patients Trial in Healthy Volunteers

Randomized, double-blind, Randomized, double-blind, Open-label, sequential-group, Trial Design placebo-controlled, sequential- placebo-controlled, sequential-SAD study group SAD study group MAD study

15 HCM patients

Study Size 48 healthy adults 60 healthy adults (2 with LVOT obstruction)

Six cohorts of eight subjects Five cohorts of 12 subjects Three cohorts: single dose of Treatment 48, 96 and 144 mg(1) each: single dose of 1, 2, 6, each(3): 28-day treatment of 12, 24 and 48 mg(2) 2, 6, 12.5, 18.5 and 25 mg(4)

Primary

Safety and tolerability of single (001 and 002) and multiple (003) oral doses of MYK-461

Endpoints

Secondary

Document pharmacokinetic (PK) profile and generate evidence of pharmacodynamic (PD) activity

Endpoints

(1) 48mg cohort (n=4 patients); 96mg cohort (n=6); 144mg cohort (n=5). (2) Each cohort randomized 6:2 MYK-461 or matching placebo.

(3) Each cohort randomized 10:2 MYK-461 or matching placebo. (4) 25mg cohort treated for 25 days.

43

MyoKardia

MYK-461-001: SAD Study in HCM Patients

Key Inclusion Criteria Key Exclusion Criteria

Age 18-60 NYHA class IV

NYHA class I—III History of clinically important atrial or

LVEF ? 65% in prior six months ventricular arrhythmias

Age (mean ± SD) 41.3 ± 14.7 years

Sex 7 male (47%), 8 female (53%) NYHA Class 13 class I (87%), 2 class II (13%) None: 3 (20%) Beta blockers: 10 (67%)

Background HCM Medication

Calcium channel blockers: 4 (27%) Disopyramide: 1 (13%)

Left Ventricular Ejection Fraction

65 ± 2.3%

(LVEF)

Maximal LV wall thickness 1.9 ± 0.42 cm

LVOT gradient (Valsalva-induced) 2 (13%) (42 and 28 mmHg)

44

MyoKardia

Favorable Safety Profile Demonstrated in Two Single Dose Trials (HCM Patients and Healthy Volunteers)

Trial Safety Details

Following administration of MYK-461, all Adverse Events (AEs) reported, except one, were mild to moderate(1)

One Serious Adverse Event (SAE) reported

SAD Trial in HCM – Occurred in the highest dose cohort (144 mg)

Patients (001) – Transient episode of hypotension and asystole, due to a vasovagal reaction

– Spontaneously resolved without lasting consequences

Most common AEs were headache, heartburn, nausea, dizziness and fatigue(2)

All AEs reported mild to moderate

No SAEs reported

SAD Trial in

Healthy Most common AEs were dizziness, headache, electrode-skin reaction (contact dermatitis) and cannula/catheter-site reaction(2)

Volunteers (002)

Mild to moderate AEs occurred at a higher numeric frequency in the placebo arm than in the drug arm

(1) One severe, non-serious AE occurred that was deemed to be not related to treatment (occurred prior to dosing).

(2) Defined as events that occurred with a frequency of n?2; all other adverse events were single occurrences.

45

MyoKardia

MYK-461 Reduces Contractility in HCM Patients

Echocardiographic Measures of One HCM Patient (48 mg dose)

Pre-dose Post-dose (2 hr)

46

MyoKardia

Clinical Proof of Mechanism: Dose-Dependent PD Response Measured by Independent Biomarkers of Contractility

SAD Results: Response at 2 Hours

) 2 0

(% e lin e s 0 a B m fro P la c e b o -2 0 e g 1 2 m g Healthy n Volunteers a 2 4 m g h C 4 8 m g -4 0 e 4 8 m g v HCM ti 9 6 m g la Patients e 1 4 4 m g

R

-6 0

L V L V V e lo c ity E je c tio n F ra c tio n a l T im e F ra c tio n S h o rte n in g In te g ra l

NOTE: Data represent mean ± SEM.

47

MyoKardia

MYK-461 Shows Dose-Dependent Effect Clearly Differentiated from Placebo; Confirms Cessation of Single Dose Drug Activity at 48+ Hours

P la c e b o

5 0 1 2 m g Healthy

2 4 m g Volunteers l 4 0 a ) 4 8 m g r % g 4 8 m g

( te 3 0 HCM e 9 6 m g

In in Patients

2 0 1 4 4 m g e l e im s 1 0 a T B

0 ty m i o c o fr -1 0 l e e V g -2 0 n T a O h -3 0

V C L -4 0 -5 0

2 h r 3 h r 4 h r 2 4 h r 4 8 h r

T im e (h )

NOTE: Data represent mean ± SEM.

48

MyoKardia

Two Patients with LVOT Obstruction Administered Single Doses of MYK-461

Phase 1 (SAD Trial in HCM Patients) LVOT Obstruction in a Study Patient

Two subjects enrolled in 001 study had a history of obstruction, and displayed a provocable LVOT pressure gradient

Each patient administered single 96 mg dose of MYK-461

Background on LVOT Obstruction

Peer-reviewed literature indicates that reducing contractility leads to a reduction in outflow tract gradients(1)

Prior experiments show ability of MYK-461 to reduce LVOT obstruction in feline model of oHCM(2)

Nistri et al. Am J Cardiol. 2012; 110:715-719: Rosing et al. Circulation. 1979;60:1201-1207; Sherrid et al. J Am Coll Cardiol. 2005; 45:1251-1258.

Data presented at the American College Veterinary Internal Medicine Forum (“Effects of a Small Molecule Modulator of Sarcomere Contractility in cats with Hypertrophics Cardiomyopathy”; June 2016).

49

MyoKardia

Single Dose Trial Experience Suggests Linkage Between Reductions in Contractility and LVOT Obstruction, Each Caused by MYK-461

1.6

Conclusions

Drug g/mL) 1.2

( ? Patient 1

0.8 Both patients’ gradients reduced

Exposure 461] Patient 2

- 0.4 following single dose of MYK-461

(PK)

[MYK 0.0 Time course of drug exposure corresponds to temporal pattern

70

of reduction in contractility (LVEF) and LVOT gradient

(%) 60

Contractility

LVEF 50 Consistent with literature and MYOK pre-clinical experiments 40 that reduction in contractility leads to reducing outflow tract gradients

40

30 Further exploration of relationship Gradient among contractility, LVOT gradient

LVOT (mmHg) 20

and other measures in PIONEER-Obstruction LVOT 10 HCM and beyond

0

0 5 10 15 20 25 Time (hours)

50

MyoKardia

Multiple Ascending Dose Trial of MYK-461 Builds Body of Evidence of Safety and Drug Effect; Guides Phase 2 Design

Objectives of Safety and tolerability of multiple oral doses of MYK-461

Document PK profile and gather evidence of PD activity MAD Trial Guide Phase 2 trial design

All Adverse Events (AEs) reported mild to moderate

No Serious Adverse Events (SAEs) reported

Summary of Most common AEs reported include: upper respiratory tract infection, Adverse Events headache, lightheadedness

Overall number of AEs (across both groups) observed in similar frequencies to those observed in previous SAD trials

Path Forward Trial has not yet been un-blinded; follow-up visits ongoing

51

MyoKardia

Repeated Daily Dosing Also Demonstrates Clinical Proof of Mechanism

MAD Results in Healthy Volunteers: Response at Day 25

) 1 0

(% e n 0 li e s a B -1 0 m ro f

-2 0 e g n a P la c e b o h -3 0 C 1 2 .5 m g e iv -4 0 1 8 .5 m g t la 2 5 m g e R

-5 0

L V L V V e lo c ity E je c tio n F ra c tio n a l T im e F ra c tio n S h o rte n in g In te g ra l

Further data on MAD results available in H1 2017

52

NOTE: Data represent mean ± SEM.

MyoKardia

Consistent PK/PD Relationship Across Phase 1 Studies Supports Dose Selection for Phase 2

25

48mg

96mg SAD Trial in HCM Patients

144mg

) 12.5mg QD

e n MAD Trial in

18.5mg QD Healthy li

e 25mg QD Volunteers

ba s 0 m r o f g e cha n

(% -25 EF V L

-50

0 500 1000 1500 2000 2500 Plasma Concentration MYK-461 (ng/ml)

53

MyoKardia

Summary and Next Steps: Advancing to Phase 2 (PIONEER-HCM)

Summary Phase 1 86 healthy volunteers and 15 HCM patients dosed with MYK-Program 461 across three Phase 1 studies(1)

Favorable safety profile observed across a meaningful dose

Safety range, including multiple doses up to 28 days

Pharmacokinetics PK profile well documented for single and multiple doses (PK) Consistent PK/PD profile to inform Phase 2 dose selection

Clinical proof of mechanism observed in HV and HCM patients; dose-dependent reduction in cardiac contractility Proof of Mechanism • Experience in two patients consistent with literature indicating that reducing contractility can reduce LVOT obstruction

(1) In addition to 22 subjects who received placebo.

54

MyoKardia

MYK-461 and the Path to Registration

Jonathan Fox, M.D., Ph.D. Chief Medical Officer

MyoKardia

MYK-461 Development is Consistent with Principles of MyoKardia Precision Medicine

Therapy that targets Designed to correct the underlying biomechanical defect causal pathway Potential for disease modification

Efficiently achieve Initial target: symptomatic, obstructive HCM

POC / first-in-class in Efficient clinical development using biomarker strategy targeted populations Orphan Drug Designation granted in April 2016

Validate mechanistic Proof of mechanism in HV and HCM patients hypothesis Broadly validates therapeutic hypothesis

Efficient clinical Mortality-based efficacy endpoints will not be required for development path registration; further detail herein

Show benefit in Experience in oHCM patients to inform future development targeted groups; expand to broader • Expand to symptomatic non-obstructive HCM patients populations (nHCM), pediatric patients

56

MyoKardia

MYK-461: From Mechanism to Clinical Benefit in Obstructive HCM

Reduce cardiac Alleviate LVOT Improved muscle contractility pressure gradient clinical benefit

?Agents that reduce contractility relieve LVOT obstruction(1)

?Obstructive HCM increases risk of severe HF or death from HF or stroke(2)

?Relief of obstruction documented to improve symptoms/function(3)

Future clinical development to focus on relationships among LVOT obstruction, clinical symptoms and functional improvement

(1) Nistri et al. Am J Cardiol. 2012; 110:715-719; Rosing et al. Circulation. 1979;60:1201-1207; Sherrid et al. J Am Coll Cardiol. 2005; 45:1251-1258 (2) Maron, M. S., Olivotto, I., Betocchi, S., Casey, S. A., Lesser, J. R., Losi, M. A., et al. (2003). Effect of Left Ventricular Outflow Tract Obstruction on Clinical Outcome in Hypertrophic Cardiomyopathy. The New England Journal of Medicine, 348(4), 295–303

57 (3) Firoozi, S. et al. “Septal myotomy-myectomy and transcoronary septal alcohol ablation in hypertrophic obstructive cardiomyopathy.”

European Heart Journal (2002) 23, 1617–1624

MyoKardia

FDA Interactions Support Precision Clinical Development Pathway

Formal interactions with the FDA (July 2016 Type C meeting) have confirmed the following:

Mortality-based efficacy endpoints will not be required for registration

Improvement in functional capacity and/or clinical symptoms are suitable endpoints for registration

A single Phase 3 pivotal study demonstrating significant improvement in functional capacity or symptoms may be adequate for approval

- Treatment duration of 12-24 weeks is appropriate

58

MyoKardia

Endpoints for Registration of MYK-461 to Measure Functional Capacity and Clinical Symptoms

Peak VO2 is the gold-standard for quantitative determination of exercise capacity

Functional

Capacity Linked to long-term prognosis in HCM patients (Peak VO2) • Correlates with clinical symptoms

Primary endpoint of other ongoing HCM trials

Clinical Will assess dyspnea (measures the primary limiting Symptoms symptom for HCM patients), NYHA class and quality of life

All above measurements to be assessed in Phase 2; final determination of primary endpoint in pivotal trial based on analysis of Phase 2 results

59

MyoKardia

Future Clinical Development to Link Mechanism to Clinical Benefit for Registration

Reduce cardiac Alleviate LVOT Improved muscle contractility pressure gradient clinical benefit

?MYK-461 ?Data showing demonstrates proof of reduction of gradient mechanism in HV and in two patients with HCM patients LVOT obstruction

Additional safety data in oHCM patients; outpatient setting PIONEER-HCM

Demonstrate consistent

Phase 2 Pilot Trial

reduction in LVOT gradient after multiple doses

Demonstrate that gradient reduction with MYK-461 confers Future Development to clinical benefit; confirm endpoint for registration

Enable Registration Establish safety and significant clinical benefit (function and/or symptoms) as a basis for registration

60

MyoKardia

PIONEER-HCM: A Phase 2 Pilot Study in Symptomatic oHCM

Evaluate safety and tolerability of repeated doses of MYK-461 in patients with symptomatic obstructive HCM

Study Goals Experience with MYK-461 in an outpatient setting

Assess level of reduction in LVOT gradient over 12 weeks of drug exposure

Begin to characterize relationship among: reductions in contractility, LVOT gradient and clinical endpoint(s)

Role in

Endpoints to include: functional capacity (peak VO2) and

Development

clinical symptoms (dyspnea, NYHA score, QOL / KCCQ)

Pathway

Enable progression to larger Ph2 study to finalize dosing and endpoints before subsequent single pivotal study

Abbreviations used: NYHA = New York Heart Association; QOL = Quality of Life; KCCQ = Kansas City Cardiomyopathy Questionnaire.

61

MyoKardia

PIONEER-HCM Study Details

Population Design

Diagnosed HCM Open-label, single-arm pilot study

Age 18-70 n=10 patients

LVOT gradient: 12 week duration followed by washout

– Resting: ?30 mmHg Primary Endpoint: Change in LVOT gradient

– Post-exercise: ?50 mmHg

LVEF ? 55% Additional objectives include: evaluation of functional capacity (CPET/pVO2) and clinical

Without background HCM symptoms (dyspnea, KCCQ, NYHA) medications Exploratory EPs include wearable biosensor measurements (e.g. iRhythm Zio®XT patch)

Screening MYK-461 Study Drug Washout

Starting Dose Adjusted Dose

Week 4: Week 12:

Screening Dose Primary Week 16

Adjustment(1) Endpoint

62 (1) At the end of week 4, pre-specified criteria allow for an increase or decrease in dose based on % decrease from baseline in LVEF.

MyoKardia

PIONEER-HCM: Expected Objectives and Timing

Assess safety and tolerability of MYK-461 in outpatient setting

Gather data that reducing contractility with MYK-461 may reduce LVOT pressure gradient after multiple doses

Objectives – Target ~15-20% relative reduction in LVEF

– Future studies to test more modest levels of LVEF reduction

Explore relationships among: contractility biomarkers, LVOT gradient, peak VO2, symptoms

Trial Six U.S. sites: Duke, Mayo Clinic (Arizona),Oregon Health Locations Sciences, Penn, Tufts, Yale

Status Study initiated; topline data expected H2 2017

63

MyoKardia

Beyond PIONEER-HCM: Efficient Clinical Development Plan to Support Registration for MYK-461 in oHCM

Treatment Potential Data Study Description Primary EP Trial Size Duration Catalyst(s) Phase 2 Pilot

LVOT Topline data (PIONEER- Effect of MYK-461 on LVOT gradient 10 12 weeks gradient H2 2017

HCM)

Initiate H2 2017 Phase 2 Characterize gradient reduction and LVOT

~60-100 12 weeks Overall duration (005 Trial) clinical benefit at multiple dose levels gradient ~1 year

Pivotal trial; confirm safety and

Phase 3 12-24 Overall duration clinical benefit in oHCM patients for Peak VO (1) ~150-200 (006 Trial) 2 weeks ~2 years registration

Ph1 SAD trial – HV

PIONEER-HCM

Ph1 SAD trial – HCM patients

Phase 2 NDA Ph1 MAD trial – HV Filing Phase 3

Today

64 (1) To be informed by Phase 2 study.

MyoKardia

Summary Development Plan for Additional Indications for MYK-461

Non-obstructive HCM (nHCM) Pediatric HCM

No medical or surgical therapies Observed in children from infancy to available other than transplant adolescence

In total, ~220,000 patients in U.S. ~1,500 children diagnosed annually(2) (~33% of HCM patients)(1)

Initiate studies based on adequate

Dosing and design to be informed by safety experience, expected to be PIONEER-HCM obtained in Phase 2

Initiate nHCM study in H2 2017

Additional information on development plan to be shared in 2017

(1) Gersh, B. J., et al. (2011). 2011 ACCF/AHA Guideline for the Diagnosis and Treatment of Hypertrophic Cardiomyopathy: 58(25), 2703–2738.

65 (2) Lipshultz, S. E., Sleeper, L. A., Towbin, J. A., Lowe, A. M., Orav, E. J., Cox, G. F., et al. (2003). The incidence of pediatric cardiomyopathy in two regions of the United States. The New England Journal of Medicine, 348(17), 1647–1655.

MyoKardia

Q&A

MyoKardia

Break

MyoKardia

JHONS HOPKINGS

MEDICINE

An Overview of

Dilated Cardiomyopathy

Daniel P. Judge, M.D.

Director, JHU Center for Inherited Heart Disease Director, Advanced HF & Transplant Fellowship Johns Hopkins University, Division of Cardiology

JOHN HOPKINS

MEDICINE

Dilated Cardiomyopathy Defined

Enlarged and weakened heart with normal wall thickness.

Particularly involving the left ventricle, often both ventricles.

Different than Hypertrophic, Restrictive, and Right Ventricular Cardiomyopathy.

Typically associated with heart failure (HFrEF), though often asymptomatic initially.

Atlas of Heart Diseases, Braunwald E (editor); Mosby 1995

JOHN HOPKINS

MEDICINE

Causes of DCM

Felker GM. N Engl J Med; 342(15):1077-84, 2000

Ischemia (CAD)

“Idiopathic”

Genetic

Hypertension

Inflammatory

Alcohol and drug abuse

Muscular dystrophy

Pregnancy Related

Toxins

Thyroid disease

Viral

Others

70

One Patient’s Journey

A 23 year-old woman with three years of exertional shortness of breath attributed to asthma….

Presented with worsening shortness of breath and “flu-like” illness over 3 months.

Treated for bronchitis—no improvement.

Developed orthopnea (shortness of breath supine).

Developed a painful, cold left foot with pallor indicating a probable blood clot in a leg artery (arterial embolism).

71

Chest X-Ray of DCM Heart

DCM

Normal

Very large heart Normal

72

Echocardiogram of DCM Heart

73

One Patient’s Journey (Cont.)

Symptoms of heart failure for three years prior to her diagnosis of DCM.

Standard medical therapy improved her LV ejection fraction from 15% to 30%.

Received a biventricular pacing defibrillator, and felt better for 4 years.

Recent worsening of heart failure; patient is being evaluated for heart transplantation.

74

Differential Diagnosis

Ischemic DCM—ruled out

Developmental malformations—ruled out

Inflammatory—ruled out

Infiltrative—ruled out

Normal tests: CBC, HIV, TFTs, Fe level

Remote viral infection?

“IDIOPATHIC” (“we have no idea”)

Family History: father died age 41: “heart attack”

75

One Patient’s Journey: Genetic Testing

Large clinical panel of genes tested for cause of her DCM.

Heterozygous TNNT2 mutation identified (p.Arg205Leu); previously published.

Also present in her affected brother.

76

Genetic DCM Defined

Approximately 20% to 35% of “idiopathic” DCM is familial.

Apparently spontaneous cases may be due to de novo mutations or recessive inheritance.

Incomplete penetrance, age-dependent phenotype, and small families also limit our ability to recognize familial cardiomyopathy.

“It’s probably viral cardiomyopathy.”

Estimate of familial DCM as a % of idiopathic DCM based on:

Cuenca S et al. Genetic basis of familial cardiomyopathy patients undergoing heart transplantation. J Heart Lung Transplant, 2016;35:625-35.

Haas J, Frese KS, Peil B, Kloos W, Keller A, Nietsch et al. Atlas of the clinical genetics of human dilated cardiomyopathy. Eur Heart J 2015;36:1123-1135.

Judge DP. Use of Genetics in the Clinical Evaluation of Cardiomyopathy. JAMA 2009; 302:2471-6.

Hershberger RE, Parks SB, Kushner JD, Li D, Ludwigsen S, Jakobs P, Nauman D, Burgess D, Partain J, Litt M. Coding sequence mutations identified in MYH7, TNNT2, SCN5A, CSRP3, LBD3, and TCAP from 313 patients with familial or idiopathic dilated cardiomyopathy. Clin Transl Sci. 2008 May; 1(1): 21–26.

77

Current International Guidelines

Genetic testing for:

DCM: Recommended if conduction delay or FH of unexpected SCD.

HCM: Recommended.

Europace (2011) 13. 1077-1109

Doi: 10.1093/europace/eur 245

EUROPACE

SOCIETY OF

CARDIOLOGY (R)

STATE OF GENETIC TESTING FOR DILATED CARDIOMYOPATHY (DCM)

Class I (is recommended)

Comprehensive or targeted (LMNA and SCN5A) DCM genetic testing is recommended for patients with DCM and significant cardiac conduction disease (i.e., first-, second-, or third-degree heart bock) and/or a family history of premature unexpected sudden death.

Mutation-specific genetic testing is recommended of family members and appropriate relatives following the identification of a DCM-causative mutation in the index case.

New guidelines are under development for cardiac genetic testing by AHA/ACC and also by HFSA in conjunction with ACMG.

78

Current Standard of Care

79

Increase Force of Contraction?

Inotropes:

Dobutamine

Milrinone

Vesnarinone

Amrinone

80

DCM Summary

There is an identifiable population of people with genetic DCM: the most common cause of idiopathic DCM.

The diagnosis is often delayed, particularly in younger patients.

Current medical therapies rely on blocking neurohormones that cause adverse LV remodeling.

There are no DCM-specific treatments for the underlying biomechanical condition.

Better therapies are needed to make hearts work more efficiently.

81

MyoKardia’s DCM Program: MYK-491

Robert McDowell, Ph.D. Senior Vice President, Drug Discovery

Myokardia

Our MYK-491 Program is Designed to Replicate the Elements that Led to Clinical Proof of Concept in MYK-461

Mechanistic understanding of underlying drivers of disease

Therapies to directly modulate targets in causal pathway

Highly predictive assays and model systems

Efficient registration path with early proof-of-concept

Continuous feedback loop to develop best-in-class solutions

MYK-461

MYK-491

In process

In process

83

Therapeutic Hypothesis for MYK-491 as a Cardiac Myosin Activator

Inadequate engaged

cross-bridges

MYK MYK-491

Increase extent of contraction

Restores cardiac output in dilated heart Potential for beneficial remodeling

Goal: improve symptoms of HF in patients with genetic DCM

Directly target mechanistic defect

Sarcomere mutations result in underpowered contraction Known causal pathway; identified genetic targets Distinct from conventional inotropes

Implications

Potential for controlled increases in contractility Minimal impact on diastole / relaxation Potential for wider therapeutic index

84

-4 MYK-491 is an Application of MyoKardia Precision Cardiovascular Medicine

Precision Medicine

Identify patient populations most likely to benefit

Use multiple methods to effectively stratify targeted group(s)

Underlying Etiology

Genetic DCM

Sarcomere mutations known to cause crossbridge defects

Clinical Features

Functional impairment

High symptomatic burden

Refractory to SOC

Mechanism of Action

Initial target: specific mutations with mechanistic rationale that MYK-491 may work in this patient group

85

Preliminary Estimates of DCM Patient Population Driven by MyoKardia Precision Medicine Approach

Idiopathic Dilated Cardiomyopathy (DCM)

~900,000

Genetic DCM (gDCM)

(~360,000)

Idiopathic DCM with unknown genetic cause(1)

DCM due to Identified Sarcomeric Mutations

(~270,000)

Other Known Mutations (~90,000)

Our proposed initial indication represents a subset of this population

(1) Represents approximately 60% of idiopathic DCM. Consists of “phenotype positive / genotype negative” patients as well as patients with genetic variants of currently unknown significance.

86

Robust Data Set Across Multiple Animal Model Systems Support Advancement into Human Trials

Healthy Dog

Heart Failure Dog

Pig

Increase extent of contraction

Stroke Volume (SV): biomarker of contractility

LVOT Velocity Time Integral (LVOT-VTI): biomarker of contractility; same parameter used in MYK-461 Phase 1

End Systolic Pressure-Volume Relationship (ESPVR): measure of inotropy

Minimal impact on diastole / relaxation

Tau: measure of diastolic relaxation

LV End Diastolic Diameter (LVEDD): measure of heart dimensions at diastole

End Diastolic Pressure-Volume Relationship (EDPVR): measure of diastolic compliance

Consistent results observed across multiple pre-clinical model systems

87

Healthy Dog: Increases Contractility without Diastolic Impact

Dose dependent increase in stroke volume (SV)

Contractility Parameters

35 30

Baseline) 25

. 20

(vs

15

SV in 10 5 change 0

% -5

0.1 1 10

Plasma concentration (µM)

Dose dependent and reversible positive inotropy

14

**

12 **

10 **

* Vehicle

(mmHg/mm) 8 1 mg/kg

6 3 mg/kg ESPVR 5 mg/kg 4

* p < 0.01

2

** p < 0.001 baseline 3h 6h 24h

Time after oral administration

Diastolic / Relaxation Parameters

In same experiments, no meaningful changes in diastolic relaxation, as measured by LVEDD (LV end diastolic diameter) and EDPVR (end diastolic pressure volume relationship)

88

Paced HF Dog: Restores Heart Function in an Animal Model of Disease without Impairing Relaxation

Contractility Parameter

Velocity Time Integral

90 *

Vehicle

80

1 mg/kg * *

70 *

Baseline 3 mg/kg

60

5 mg/kg *

50 from 40 *

30 20

Change 10

0

% -10

0h 3h 6h

•Dose dependent increase in contractility

* p < 0.05

Diastolic / Relaxation Parameter

Tau

20 Vehicle 1 mg/kg

10 3 mg/kg

Baseline 5 mg/kg from 0 Change -10

-20

%

0h 3h 6h

•No significant impact on diastolic relaxation

89

Pig Model: Increases Systolic Function without Impairment of Diastole in a Second Large Mammal Model

Contractility Parameter

Stroke Volume

(%) 20

MYK-491 (n=7) * ** ** Control (n=6)

baseline 10 from 0

* p < 0.05 ** p < 0.01

Change -10

Bsl 0.16 0.33 0.5 0.66 0.84 1 mg/kg

•Dose dependent increase in contractility

Diastolic / Relaxation Parameter

(%) 15 Tau

MYK-491 (n=7)

10

Control (n=6)

Baseline 5 0 from -5 -10 Change -15

Bsl 0.16 0.33 0.5 0.66 0.84 1 mg/kg

•No significant impact on diastolic relaxation

90

91

Baseline 1 mg/kg IV infusion

Imaging Studies in Pig Model Show that MYK-491 Can Increase Contractility without Impairing Diastole 91

92 Freeze Frames of Imaging Studies in Pig Model Highlight Increased Contraction without Diastolic Impairment

Baseline 1 mg/kg IV infusion End of Systole

End of Diastole

MYK-491 Expected to Follow a Clinical Development Pathway Informed by Principles of MyoKardia Precision Medicine Trial # Description Trial Objective(s) Trial Initiation Topline Results

001 Ph1 Single ascending dose (SAD)

• Safety, tolerability, Proof of Mechanism (POM)

H1 2017 Q3 2017

002 Ph1 Multiple ascending dose (MAD)

• Safety, tolerability, POM for repeated dosing

Guide dosing in Phase 2 and beyond

H2 2017 TBA

Research Directions Toward Vision 2020

Mike Graziano, Ph.D.

Vice President, Research Biology

Mechanistic understanding of underlying drivers of disease

Highly predictive assays and model systems

Continuous feedback loop to develop best-in-class

Therapies to directly modulate targets in causal pathway MYK-461 MYK-491 Future Programs

In process

In process

MyoKardia Generating Valuable Insights from Key Investments in Product Engine

Precision medicine approach

Mechanism conserved throughout discovery and development

Efficient clinical development

Clinical insight to causality (genetics)

Molecular targets in causal pathway

Specifically targeted therapies for defined patient groups

Imaging-based biomarker strategy

Potential for faster, smaller, more cost-effective clinical trials

In vitro

Small animals

Large animals

Healthy volunteers

HCM/DCM patients

96

Each pathology can be targeted using multiple mechanisms

Identify the most appropriate mechanism for each patient

Leadership of our disease space with multiple best-in-class agents

Deep research investments to identify causal mechanism

Test underlying assumptions through our precision approach

Potential for combination strategies

Various methods of patient segmentation

Invest in translational tools (cellular, SHaRe, in vivo) to map mechanism to patient segment

Sustainable competitive advantage

Capitalize on position at “center of ecosystem”

Innovator in diagnosing, monitoring and treating patients

Efficient and iterative development plan to achieve best-in-class

Rapidly advance first-in-class agents to clinic

Clinical, translational experience to guide discovery and development (continuous feedback loop)

Leader in the Science and Treatment of Heritable Cardiomyopathies: Expected Implications and Benefits

97

Path to Leadership in the Disease Space: Best-in-Class Therapies to Treat Characteristic Pathologies

Impaired relaxation

Excessive contraction

Inadequate

contraction Underlying Pathology Dilated cardiomyopathy (DCM) Hypertrophic cardiomyopathy (HCM)

Initial Disease Indications

98

Therapeutic Hypothesis

Improve relaxation kinetics

Reduce power output Enhance power output LUS-1 MYK-491

HCM-2

… and potential future disease area expansions beyond heritable cardiomyopathies

MYK-461

Myosin light chain ? Myosin heavy chain

Troponin T

? Tropomyosin

Troponin I

Actin Myosin binding protein C Current clinical-stage programs: Formation of myosin-actin crossbridge MyoKardia pipeline programs based on validated genetic targets

Plus: additional validated targets

Significant Opportunity for Important Therapies Remains in Our Core Area of Expertise

Targeting regulatory proteins: more subtle modulation of contraction; potential partial activator/inhibitor

99

Myosin-actin crossbridge

Our Precision Medicine Strategy Has Potential Applicability Beyond Our Initial Vision 2020 Targets 100 Vision 2020

Leadership in our disease area(s)

Focus on heritable cardiomyopathies

Future Applications

Expansion to serve additional, broader patient populations

Apply precision approach to sub-divide broad HF

U n derlying Etiology Clinical Features

Mechanism of Action MyoKardia Precision Cardiovascular Medicine

Closing Remarks

Tassos Gianakakos

Chief Executive Officer

Key Takeaways From Today 102 MYK-461 and HCM

Mortality-based efficacy endpoints will not be required for registration

Improvement in functional capacity and/or clinical symptoms are suitable endpoints for registration

Single Phase 3 pivotal study demonstrating significant improvement may be adequate for approval

PIONEER-HCM de-risks overall program; efficiently enables studies to support determination of dose and endpoint

Initiate Phase 2 trial in nHCM in H2 2017

MYK-491 and DCM

Strong pre-clinical rationale for MYK-491 to advance into Phase 1 in H1 2017

Second clinical candidate further validates our precision medicine product engine

MyoKardia Corporate

Poised to execute on Vision 2020

Multiple data catalysts in 2017

Research group provides strong foundation for future growth

2016 2017

Value Inflection Catalysts From Multiple Programs Throughout 2016 and 2017

HCM / MYK-461 Milestone

DCM / MYK-491 Milestone Corporate Milestone

Q3 2017:

Topline data from Phase 1 SAD trial of MYK-491 H2 2016: Enroll first patient in PIONEER-HCM trial

H2 2017:

Topline data from PIONEER-HCM H2 2017: Initiate Phase 2 clinical trial of MYK-461 in oHCM

H2 2017:

Initiate clinical trial of MYK-461 in nHCM population

103

H1 2017:

$25 million cash milestone from Sanofi for MYK-491 IND filing; initiate Phase 1 trial Early 2017: Sanofi partnership continuation and $45 million cash milestone

Q&A

MyoKardia