Exhibit 99.1 Sarcomere Directed Therapies EMPOWERING MUSCLE EMPOWERING LIVES John, diagnosed with heart failure Jillian, diagnosed with HCM Chuck, diagnosed with ALSExhibit 99.1 Sarcomere Directed Therapies EMPOWERING MUSCLE EMPOWERING LIVES John, diagnosed with heart failure Jillian, diagnosed with HCM Chuck, diagnosed with ALS
Disclaimer This Presentation contains forward-looking statements for purposes of the Private Securities Litigation Reform Act of 1995 (the “Act”). Cytokinetics disclaims any intent or obligation to update these forward-looking statements, and claims the protection of the Act's Safe Harbor for forward-looking statements. Examples of such statements include, but are not limited to, statements related Cytokinetics’ and its partners’ research and development and commercial readiness activities, including the initiation, conduct, design, enrollment, progress, continuation, completion, timing and results of clinical trials, projections regarding growing prevalence, low survival rates and market opportunity in heart failure; Cytokinetics’ commercial readiness for omecamtiv mecarbil; Cytokinetics’ ability to earn and receive milestone payments; the timing and results of clinical trials of AMG 594 and CK- 274; the timing of any potential commercial launch of our product candidates, if approved; commercial opportunities for our product candidates; Cytokinetics’ cash runway; interactions with the FDA; the properties, potential benefits and commercial potential of CK-274, omecamtiv mecarbil, AMG 594, reldesemtiv and Cytokinetics’ other drug candidates. Such statements are based on management's current expectations; but actual results may differ materially due to various risks and uncertainties, including, but not limited to, potential difficulties or delays in the development, testing, regulatory approvals for trial commencement, progression or product sale or manufacturing, or production of Cytokinetics’ drug candidates that could slow or prevent clinical development or product approval, including risks that current and past results of clinical trials or preclinical studies may not be indicative of future clinical trial results, patient enrollment for or conduct of clinical trials may be difficult or delayed, Cytokinetics’ drug candidates may have adverse side effects or inadequate therapeutic efficacy, the FDA or foreign regulatory agencies may delay or limit Cytokinetics’ or its partners’ ability to conduct clinical trials, and Cytokinetics may be unable to obtain or maintain patent or trade secret protection for its intellectual property; Astellas’, Amgen’s or Ji Xing’s decisions with respect to the design, initiation, conduct, timing and continuation of development activities for reldesemtiv, omecamtiv mecarbil or CK-274, respectively; Cytokinetics’ ability to satisfy and conditions to the sale of its royalty interest in mavacamten or disbursement of funding from RTW; Cytokinetics may incur unanticipated research, development and other costs or be unable to obtain financing necessary to conduct development of its products; standards of care may change, rendering Cytokinetics’ drug candidates obsolete; competitive products or alternative therapies may be developed by others for the treatment of indications Cytokinetics’ drug candidates and potential drug candidates may target; and risks and uncertainties relating to the timing and receipt of payments from its partners, including milestones and royalties on future potential product sales under Cytokinetics’ collaboration agreements with such partners. These forward-looking statements speak only as of the date they are made, and Cytokinetics undertakes no obligation to subsequently update any such statement, except as required by law. For further information regarding these and other risks related to Cytokinetics’ business, investors should consult Cytokinetics’ filings with the Securities and Exchange Commission. O V E R V I E W C A R D I A C C A N D I D A TE S S K E L E T A L C A N D I D A TE S C O R P O R A TE P R OF I L E 2Disclaimer This Presentation contains forward-looking statements for purposes of the Private Securities Litigation Reform Act of 1995 (the “Act”). Cytokinetics disclaims any intent or obligation to update these forward-looking statements, and claims the protection of the Act's Safe Harbor for forward-looking statements. Examples of such statements include, but are not limited to, statements related Cytokinetics’ and its partners’ research and development and commercial readiness activities, including the initiation, conduct, design, enrollment, progress, continuation, completion, timing and results of clinical trials, projections regarding growing prevalence, low survival rates and market opportunity in heart failure; Cytokinetics’ commercial readiness for omecamtiv mecarbil; Cytokinetics’ ability to earn and receive milestone payments; the timing and results of clinical trials of AMG 594 and CK- 274; the timing of any potential commercial launch of our product candidates, if approved; commercial opportunities for our product candidates; Cytokinetics’ cash runway; interactions with the FDA; the properties, potential benefits and commercial potential of CK-274, omecamtiv mecarbil, AMG 594, reldesemtiv and Cytokinetics’ other drug candidates. Such statements are based on management's current expectations; but actual results may differ materially due to various risks and uncertainties, including, but not limited to, potential difficulties or delays in the development, testing, regulatory approvals for trial commencement, progression or product sale or manufacturing, or production of Cytokinetics’ drug candidates that could slow or prevent clinical development or product approval, including risks that current and past results of clinical trials or preclinical studies may not be indicative of future clinical trial results, patient enrollment for or conduct of clinical trials may be difficult or delayed, Cytokinetics’ drug candidates may have adverse side effects or inadequate therapeutic efficacy, the FDA or foreign regulatory agencies may delay or limit Cytokinetics’ or its partners’ ability to conduct clinical trials, and Cytokinetics may be unable to obtain or maintain patent or trade secret protection for its intellectual property; Astellas’, Amgen’s or Ji Xing’s decisions with respect to the design, initiation, conduct, timing and continuation of development activities for reldesemtiv, omecamtiv mecarbil or CK-274, respectively; Cytokinetics’ ability to satisfy and conditions to the sale of its royalty interest in mavacamten or disbursement of funding from RTW; Cytokinetics may incur unanticipated research, development and other costs or be unable to obtain financing necessary to conduct development of its products; standards of care may change, rendering Cytokinetics’ drug candidates obsolete; competitive products or alternative therapies may be developed by others for the treatment of indications Cytokinetics’ drug candidates and potential drug candidates may target; and risks and uncertainties relating to the timing and receipt of payments from its partners, including milestones and royalties on future potential product sales under Cytokinetics’ collaboration agreements with such partners. These forward-looking statements speak only as of the date they are made, and Cytokinetics undertakes no obligation to subsequently update any such statement, except as required by law. For further information regarding these and other risks related to Cytokinetics’ business, investors should consult Cytokinetics’ filings with the Securities and Exchange Commission. O V E R V I E W C A R D I A C C A N D I D A TE S S K E L E T A L C A N D I D A TE S C O R P O R A TE P R OF I L E 2
Sarcomere Directed Therapies OUR MISSION To bring forward new medicines to improve the healthspan of people with devastating cardiovascular and neuromuscular diseases of impaired muscle function. 3Sarcomere Directed Therapies OUR MISSION To bring forward new medicines to improve the healthspan of people with devastating cardiovascular and neuromuscular diseases of impaired muscle function. 3
Achieve regulatory approvals for at least two drugs arising from our pipeline Build commercial capabilities to market and sell our medicines reflective of their innovation and value VISION Generate sustainable and growing Our vision is to be the revenues from product sales leading muscle biology biopharma company that meaningfully improves the lives of patients with diseases of impaired muscle function through access to our Double our development pipeline to pioneering medicines Leading with Science, include ten therapeutic programs As always, we will support disease advocacy groups elevating the patient voice and live by our values of Expand our discovery platform to muscle integrity, fairness and compassion in all that we do. energetics, growth and metabolism Be the science-driven company people want to join and partner with O V E R V I E W C A R D I A C C A N D I D A TE S S K E L E T A L C A N D I D A TE S C O R P O R A TE P R OF I L E 4Achieve regulatory approvals for at least two drugs arising from our pipeline Build commercial capabilities to market and sell our medicines reflective of their innovation and value VISION Generate sustainable and growing Our vision is to be the revenues from product sales leading muscle biology biopharma company that meaningfully improves the lives of patients with diseases of impaired muscle function through access to our Double our development pipeline to pioneering medicines Leading with Science, include ten therapeutic programs As always, we will support disease advocacy groups elevating the patient voice and live by our values of Expand our discovery platform to muscle integrity, fairness and compassion in all that we do. energetics, growth and metabolism Be the science-driven company people want to join and partner with O V E R V I E W C A R D I A C C A N D I D A TE S S K E L E T A L C A N D I D A TE S C O R P O R A TE P R OF I L E 4
How Do We Get There? Conduct rigorous, step-wise clinical research Exploit muscle biology roots De-risk development programs Measure pharmacodynamics of to increase POS muscle function Optimize PK/PD relationships Develop first-in-class, next-in class, best-in-class compounds Maintain continuity of LEAD WITH METHODICALLY engagement with leading KOLs Expand contractility focus to SCIENCE INVESTIGATE muscle energetics, metabolism Adopt customer-centric approach to portfolio management Engage early and often BUILD A THINK LIKE for input and guidance Pioneer and lead: innovate, integrate and scale FRANCHISE A PATIENT Elevate patient voice Extend and expand through Improve function, lifecycle management performance and healthspan Continually pursue Adapt trial design to facilitate back-ups, follow-ons, next-gen participation drug candidates O V E R V I E W C A R D I A C C A N D I D A TE S S K E L E T A L C A N D I D A TE S C O R P O R A TE P R OF I L E 5How Do We Get There? Conduct rigorous, step-wise clinical research Exploit muscle biology roots De-risk development programs Measure pharmacodynamics of to increase POS muscle function Optimize PK/PD relationships Develop first-in-class, next-in class, best-in-class compounds Maintain continuity of LEAD WITH METHODICALLY engagement with leading KOLs Expand contractility focus to SCIENCE INVESTIGATE muscle energetics, metabolism Adopt customer-centric approach to portfolio management Engage early and often BUILD A THINK LIKE for input and guidance Pioneer and lead: innovate, integrate and scale FRANCHISE A PATIENT Elevate patient voice Extend and expand through Improve function, lifecycle management performance and healthspan Continually pursue Adapt trial design to facilitate back-ups, follow-ons, next-gen participation drug candidates O V E R V I E W C A R D I A C C A N D I D A TE S S K E L E T A L C A N D I D A TE S C O R P O R A TE P R OF I L E 5
Pipeline of Novel Muscle-Directed Drug Candidates Research Pre-Clinical Phase 1 Phase 2 Phase 3 CARDIAC MUSCLE Omecamtiv Mecarbil (Heart Failure) AMGEN COLLABORATION CK-274 (oHCM, nHCM, HFpEF) RTW / JI XING COLLABORATION CK-271 AMG 594 (Heart Failure, other) AMGEN COLLABORATION SKELETAL MUSCLE Reldesemtiv (ALS)* CK-601 Additional Skeletal Muscle Activators ASTELLAS COLLABORATION OTHER Myosin-Targeted Muscle Biology Directed Research Troponin-Targeted Research * Astellas provides co-funding in exchange for low single-digit royalty Investigational products – not approved as safe or effective for any indication O V E R V I E W C A R D I A C C A N D I D A TE S S K E L E T A L C A N D I D A TE S C O R P O R A TE P R OF I L E 6Pipeline of Novel Muscle-Directed Drug Candidates Research Pre-Clinical Phase 1 Phase 2 Phase 3 CARDIAC MUSCLE Omecamtiv Mecarbil (Heart Failure) AMGEN COLLABORATION CK-274 (oHCM, nHCM, HFpEF) RTW / JI XING COLLABORATION CK-271 AMG 594 (Heart Failure, other) AMGEN COLLABORATION SKELETAL MUSCLE Reldesemtiv (ALS)* CK-601 Additional Skeletal Muscle Activators ASTELLAS COLLABORATION OTHER Myosin-Targeted Muscle Biology Directed Research Troponin-Targeted Research * Astellas provides co-funding in exchange for low single-digit royalty Investigational products – not approved as safe or effective for any indication O V E R V I E W C A R D I A C C A N D I D A TE S S K E L E T A L C A N D I D A TE S C O R P O R A TE P R OF I L E 6
Corporate Development Strategy Multiple product launches catalyze revenue growth Organizational capacity Diversified commercial cash flows sustain profitability Commercial infrastructure Propriety research & development 2020 2021 2022 2023 2024 2025 • Potential for $100M • Potential for $300M • Escalating double-• Potential for $300M • Retained commercial short-term milestones pre-commercial digit royalties in post-commercial rights and economics milestones omecamtiv mecarbil milestones CK-274 omecamtiv mecarbil reldesemtiv oHCM, nHCM Heart Failure ALS COMMITTED CAPITAL FOR CO-PROMOTION: CO-FUNDING PHASE 3 DEVELOPMENT/LICENSING NORTH AMERICA CLINICAL DEVELOPMENT COLLABORATION IN CHINA Above illustrative timelines are based on current assumptions and projections. All such timelines are subject to change and may be materially delayed based on a variety of factors, including patient enrollment, clinical trial results, regulatory review, our partners' ability to manufacture products and other factors. O V E R V I E W C A R D I A C C A N D I D A TE S S K E L E T A L C A N D I D A TE S C O R P O R A TE P R OF I L E 7Corporate Development Strategy Multiple product launches catalyze revenue growth Organizational capacity Diversified commercial cash flows sustain profitability Commercial infrastructure Propriety research & development 2020 2021 2022 2023 2024 2025 • Potential for $100M • Potential for $300M • Escalating double-• Potential for $300M • Retained commercial short-term milestones pre-commercial digit royalties in post-commercial rights and economics milestones omecamtiv mecarbil milestones CK-274 omecamtiv mecarbil reldesemtiv oHCM, nHCM Heart Failure ALS COMMITTED CAPITAL FOR CO-PROMOTION: CO-FUNDING PHASE 3 DEVELOPMENT/LICENSING NORTH AMERICA CLINICAL DEVELOPMENT COLLABORATION IN CHINA Above illustrative timelines are based on current assumptions and projections. All such timelines are subject to change and may be materially delayed based on a variety of factors, including patient enrollment, clinical trial results, regulatory review, our partners' ability to manufacture products and other factors. O V E R V I E W C A R D I A C C A N D I D A TE S S K E L E T A L C A N D I D A TE S C O R P O R A TE P R OF I L E 7
Omecamtiv Mecarbil: Collaborations & Agreements Amgen & Royalty Pharma Amgen Collaboration Royalty Monetization Purchase Option: 2006 Exercise Option Ex-Japan: 2009 Royalty Pharma paid $100M** for 4.5% royalty on worldwide sales of omecamtiv mecarbil: 2017 Expanded to Include Japan/Purchase Equity: 2013 Received >$220M over 13 Years Commercialization:• Royalty rate may increase up to Amgen responsible Cytokinetics gains right additional 1% associated with timing of for development and to co-promote omecamtiv • Cytokinetics may receive escalating US approval commercialization subject double-digit royalties mecarbil, if approved, in • Cytokinetics agreed to exercise option to Cytokinetics’ institutional care settings • Cytokinetics to co-fund Phase 3 to co-invest $40M in Ph 3 development participation rights* in North America, with development program program in exchange for up to reimbursement from • Co-fund enables co-promote NA incremental 4% royalty on increasing Cytokinetics could Amgen for certain sales worldwide sales outside of Japan earn over $600M in • Cytokinetics reimbursed for certain force activities milestone payments• Cytokinetics retains right to receive sales force activities >$600M in additional potential milestone Joint commercial payments and escalating double-digit operating team responsible royalties that may exceed 20% on tiered for commercialization worldwide sales outside Japan; lower program royalty rate in Japan *Comprised of $90M for royalty purchase and $10M for common stock purchase. *Servier has a sub-license from Amgen to commercialize omecamtiv mecarbil in Europe and certain other countries. O V E R V I E W C A R D I A C C A N D I D A TE S S K E L E T A L C A N D I D A TE S C O R P O R A TE P R OF I L E 8Omecamtiv Mecarbil: Collaborations & Agreements Amgen & Royalty Pharma Amgen Collaboration Royalty Monetization Purchase Option: 2006 Exercise Option Ex-Japan: 2009 Royalty Pharma paid $100M** for 4.5% royalty on worldwide sales of omecamtiv mecarbil: 2017 Expanded to Include Japan/Purchase Equity: 2013 Received >$220M over 13 Years Commercialization:• Royalty rate may increase up to Amgen responsible Cytokinetics gains right additional 1% associated with timing of for development and to co-promote omecamtiv • Cytokinetics may receive escalating US approval commercialization subject double-digit royalties mecarbil, if approved, in • Cytokinetics agreed to exercise option to Cytokinetics’ institutional care settings • Cytokinetics to co-fund Phase 3 to co-invest $40M in Ph 3 development participation rights* in North America, with development program program in exchange for up to reimbursement from • Co-fund enables co-promote NA incremental 4% royalty on increasing Cytokinetics could Amgen for certain sales worldwide sales outside of Japan earn over $600M in • Cytokinetics reimbursed for certain force activities milestone payments• Cytokinetics retains right to receive sales force activities >$600M in additional potential milestone Joint commercial payments and escalating double-digit operating team responsible royalties that may exceed 20% on tiered for commercialization worldwide sales outside Japan; lower program royalty rate in Japan *Comprised of $90M for royalty purchase and $10M for common stock purchase. *Servier has a sub-license from Amgen to commercialize omecamtiv mecarbil in Europe and certain other countries. O V E R V I E W C A R D I A C C A N D I D A TE S S K E L E T A L C A N D I D A TE S C O R P O R A TE P R OF I L E 8
CK-3773274: Collaborations & Agreements RTW Investments, LP & Ji Xing Pharmaceuticals Limited RTW & Ji Xing Pharma Licensing Collaboration, Funding Commitments & Royalty Monetization RTW Investments committed capital, funding and sale proceeds of $250M to Cytokinetics Ji Xing Pharma to develop & commercialize CK-274 in China, subject to royalties and up to $200M in milestone payments RTW Investments purchases equity and agrees to purchase royalty; provides access to capital for development of CK-274 Ji Xing Pharma RTW: Funding for Development of CK-274 RTW: Other Purchases Ji Xing to develop & commercialize Cytokinetics receives options for additional funding for RTW agrees to purchase Cytokinetics’ CK-274 in Greater China and Taiwan further development of CK-274 in HCMs: royalty rights on future sales of mavacamten for $85M • Eligible for $45M in each of 2 tranches (upon initiation Cytokinetics receives $25M upfront; of global registration programs in oHCM and nHCM) in eligible to receive $200M in RTW purchases $50M of exchange for 2% royalty on sales in U.S. & certain development & commercial Cytokinetics’ common stock at $25 European countries milestones & double-digit royalties on per share sales of CK-274 in licensed territory• If full $90M received, Cytokinetics pays RTW 4% royalty on sales of CK-274 in U.S. & certain European countries, subject to royalty reductions for potential other indications I N T R O A C T I V A T E I N H I BI T E M P O WE R C L O S I N G 9CK-3773274: Collaborations & Agreements RTW Investments, LP & Ji Xing Pharmaceuticals Limited RTW & Ji Xing Pharma Licensing Collaboration, Funding Commitments & Royalty Monetization RTW Investments committed capital, funding and sale proceeds of $250M to Cytokinetics Ji Xing Pharma to develop & commercialize CK-274 in China, subject to royalties and up to $200M in milestone payments RTW Investments purchases equity and agrees to purchase royalty; provides access to capital for development of CK-274 Ji Xing Pharma RTW: Funding for Development of CK-274 RTW: Other Purchases Ji Xing to develop & commercialize Cytokinetics receives options for additional funding for RTW agrees to purchase Cytokinetics’ CK-274 in Greater China and Taiwan further development of CK-274 in HCMs: royalty rights on future sales of mavacamten for $85M • Eligible for $45M in each of 2 tranches (upon initiation Cytokinetics receives $25M upfront; of global registration programs in oHCM and nHCM) in eligible to receive $200M in RTW purchases $50M of exchange for 2% royalty on sales in U.S. & certain development & commercial Cytokinetics’ common stock at $25 European countries milestones & double-digit royalties on per share sales of CK-274 in licensed territory• If full $90M received, Cytokinetics pays RTW 4% royalty on sales of CK-274 in U.S. & certain European countries, subject to royalty reductions for potential other indications I N T R O A C T I V A T E I N H I BI T E M P O WE R C L O S I N G 9
Reldesemtiv: Collaborations & Agreements Astellas Collaboration Cytokinetics has exclusive rights to reldesemtiv, CK-601 and other FSRAs Cytokinetics has exclusive control and responsibility for development and commercialization of reldesemtiv, CK-601 and other fast skeletal regulatory activators Astellas to pay certain costs up to $12M for potential Phase 3 clinical trial of reldesemtiv in ALS Cytokinetics to pay Astellas low- to mid- single digit royalty on sales of reldesemtiv in certain countries Astellas funds joint research program with 15 Cytokinetics employees through 2020 O V E R V I E W C A R D I A C C A N D I D A TE S S K E L E T A L C A N D I D A TE S C O R P O R A TE P R OF I L E 10Reldesemtiv: Collaborations & Agreements Astellas Collaboration Cytokinetics has exclusive rights to reldesemtiv, CK-601 and other FSRAs Cytokinetics has exclusive control and responsibility for development and commercialization of reldesemtiv, CK-601 and other fast skeletal regulatory activators Astellas to pay certain costs up to $12M for potential Phase 3 clinical trial of reldesemtiv in ALS Cytokinetics to pay Astellas low- to mid- single digit royalty on sales of reldesemtiv in certain countries Astellas funds joint research program with 15 Cytokinetics employees through 2020 O V E R V I E W C A R D I A C C A N D I D A TE S S K E L E T A L C A N D I D A TE S C O R P O R A TE P R OF I L E 10
Commercialization Strategy Leveraging partnership with Amgen to finance the build of our commercial business Amgen to reimburse Cytokinetics’ commercialization Focus to Concentrated Customer Segments costs in North America (e.g. Centers of Excellence) Potential royalties and milestone payments from Amgen expected to support Cytokinetics’ commercialization of CK-274, reldesemtiv in North America and Europe omecamtiv mecarbil Heart Failure CK-274 reldesemtiv oHCM, nHCM ALS O V E R V I E W C A R D I A C C A N D I D A TE S S K E L E T A L C A N D I D A TE S C O R P O R A TE P R OF I L E 11Commercialization Strategy Leveraging partnership with Amgen to finance the build of our commercial business Amgen to reimburse Cytokinetics’ commercialization Focus to Concentrated Customer Segments costs in North America (e.g. Centers of Excellence) Potential royalties and milestone payments from Amgen expected to support Cytokinetics’ commercialization of CK-274, reldesemtiv in North America and Europe omecamtiv mecarbil Heart Failure CK-274 reldesemtiv oHCM, nHCM ALS O V E R V I E W C A R D I A C C A N D I D A TE S S K E L E T A L C A N D I D A TE S C O R P O R A TE P R OF I L E 11
Sarcomere Directed Drug Development CARDIAC MUSCLE Omecamtiv Mecarbil AMG 594 CK-274, CK-271 12Sarcomere Directed Drug Development CARDIAC MUSCLE Omecamtiv Mecarbil AMG 594 CK-274, CK-271 12
Tremendous Need Exists to Improve CV Care Novel CV drugs are desperately needed to improve patient healthspan Heart Disease the Leading CV Disease the Leading Lack of innovation Exists Cause of Death in the US Category in Healthcare Spend Across CV Conditions #1 Rare diseases #1 Heart disease #1 Cardiovascular (185) ($327B) (211 drugs approved) #2 Neurologic disease #2 Cancer #2 Musculoskeletal (152) ($300B) (139 drugs approved) #3 Cancer #3 Respiratory (49) #3 Respiratory ($231B) (133 drugs approved) #10 Cardiovascular #4 Stroke #4 Endocrine (38) ($227B) (43 drugs approved) … and just 4 drugs for HF 2018 US Deaths per 100,000 Standard Population 2019 US Expenditure by Disease Category # of Approved Drugs since 2010 Source: NCHS Data Brief, No. 355 January 2020, Peterson-KFF, Health System Tracker, PharmaProjects. O V E R V I E W C A R D I A C C A N D I D A T E S S K E L E T A L C A N D I D A TE S C O R P O R A TE P R OF I L E 13Tremendous Need Exists to Improve CV Care Novel CV drugs are desperately needed to improve patient healthspan Heart Disease the Leading CV Disease the Leading Lack of innovation Exists Cause of Death in the US Category in Healthcare Spend Across CV Conditions #1 Rare diseases #1 Heart disease #1 Cardiovascular (185) ($327B) (211 drugs approved) #2 Neurologic disease #2 Cancer #2 Musculoskeletal (152) ($300B) (139 drugs approved) #3 Cancer #3 Respiratory (49) #3 Respiratory ($231B) (133 drugs approved) #10 Cardiovascular #4 Stroke #4 Endocrine (38) ($227B) (43 drugs approved) … and just 4 drugs for HF 2018 US Deaths per 100,000 Standard Population 2019 US Expenditure by Disease Category # of Approved Drugs since 2010 Source: NCHS Data Brief, No. 355 January 2020, Peterson-KFF, Health System Tracker, PharmaProjects. O V E R V I E W C A R D I A C C A N D I D A T E S S K E L E T A L C A N D I D A TE S C O R P O R A TE P R OF I L E 13
Heart Failure: Growing Prevalence and Low Survival Rates 6 million people have heart failure in the United States Prevalence Expected to HF Survival Rates Worse than Some Increase by 46% from 2012 – 2030 Prevalent Cancers Men Women 10 9 8 7 6 +46% 5 8.3 4 3 5.7 2 1 0 2012 2030 Mozzafarian, et al. Circulation 2016; 133: e38-360 Mamas et al. Eur J Heart Fail. 2017 Sep;19(9):1095-104 O V E R V I E W C A R D I A C C A N D I D A T E S S K E L E T A L C A N D I D A TE S C O R P O R A TE P R OF I L E 14 Number of cases (M)Heart Failure: Growing Prevalence and Low Survival Rates 6 million people have heart failure in the United States Prevalence Expected to HF Survival Rates Worse than Some Increase by 46% from 2012 – 2030 Prevalent Cancers Men Women 10 9 8 7 6 +46% 5 8.3 4 3 5.7 2 1 0 2012 2030 Mozzafarian, et al. Circulation 2016; 133: e38-360 Mamas et al. Eur J Heart Fail. 2017 Sep;19(9):1095-104 O V E R V I E W C A R D I A C C A N D I D A T E S S K E L E T A L C A N D I D A TE S C O R P O R A TE P R OF I L E 14 Number of cases (M)
High Mortality and Hospital Readmission Rates 1,2 Acute heart failure is the most frequent cause of hospitalization in people > 65 5 years 3,7,8 post-discharge 1 year 7,9 post-discharge ~ 40-50% 60 days mortality 7 post-discharge ~ 20-30% after 5 years Initial mortality Hospitalization ~ 25-50% 1 of 2 after 1 year of patients expire or hospitalized are re-hospitalized HF patients are readmitted 5 within 6 months <1 month <6 months <12 months 4,6 5 3,10 post-discharge post-discharge post-discharge 24% 44% 66% readmitted readmitted readmitted 1, Adams et al. Am Heart J 2006; 149:209-16 6. Krumholz et al. Circ Cardiovasc Qual Outcomes 2009;2(5):407-13 2. Chen et al. JAMA 2011;306:1669-78 7. Loehr et al. Am J Cardiol 2008;101:1016-22 3. Dickstein et al. Eur Heart J 2008;29:2388-442 8. Roger et al. Circulation 2012;125:32-220 4. Korda,, et al. BMC Health Serv Res. 2017;21;17(1):220. 9. Shahar, et al. J Card Fail 2004; 10(5):374-9 5. Krumholz et al. Arch Intern Med 1997;15799 – 105 10. Whellan et al. Circulation 2010 Jan;3(1):33-40 O V E R V I E W C A R D I A C C A N D I D A T E S S K E L E T A L C A N D I D A TE S C O R P O R A TE P R OF I L E 15High Mortality and Hospital Readmission Rates 1,2 Acute heart failure is the most frequent cause of hospitalization in people > 65 5 years 3,7,8 post-discharge 1 year 7,9 post-discharge ~ 40-50% 60 days mortality 7 post-discharge ~ 20-30% after 5 years Initial mortality Hospitalization ~ 25-50% 1 of 2 after 1 year of patients expire or hospitalized are re-hospitalized HF patients are readmitted 5 within 6 months <1 month <6 months <12 months 4,6 5 3,10 post-discharge post-discharge post-discharge 24% 44% 66% readmitted readmitted readmitted 1, Adams et al. Am Heart J 2006; 149:209-16 6. Krumholz et al. Circ Cardiovasc Qual Outcomes 2009;2(5):407-13 2. Chen et al. JAMA 2011;306:1669-78 7. Loehr et al. Am J Cardiol 2008;101:1016-22 3. Dickstein et al. Eur Heart J 2008;29:2388-442 8. Roger et al. Circulation 2012;125:32-220 4. Korda,, et al. BMC Health Serv Res. 2017;21;17(1):220. 9. Shahar, et al. J Card Fail 2004; 10(5):374-9 5. Krumholz et al. Arch Intern Med 1997;15799 – 105 10. Whellan et al. Circulation 2010 Jan;3(1):33-40 O V E R V I E W C A R D I A C C A N D I D A T E S S K E L E T A L C A N D I D A TE S C O R P O R A TE P R OF I L E 15
High Economic Burden of Heart Failure 1,2 Heart failure costs ~$123 billion annually, representing 33% of total Medicare budget Inpatient Admission Rates for HF Patients 1 6X Higher than Non-HF Patients 1800 1600 1400 1200 Heart failure is the most 1000 frequent diagnosis for 1,664 800 hospitalized Medicare 6X 1,2 600 patients in the US 400 200 272 0 Non-Heart Failure Heart Failure 1. Milliman Analysis of Medicare 5% Sample 2011-2012 (2012 index year, 2011 look back year) 2. Milliman Analysis of Medicare 5% Sample (2014 index year, 2013 look back year) and Office of the Actuary 2016 Board of Trustees Report. The costs only include Part A & B costs O V E R V I E W C A R D I A C C A N D I D A T E S S K E L E T A L C A N D I D A TE S C O R P O R A TE P R OF I L E 16 Annual Inpatient Admits per 1,000High Economic Burden of Heart Failure 1,2 Heart failure costs ~$123 billion annually, representing 33% of total Medicare budget Inpatient Admission Rates for HF Patients 1 6X Higher than Non-HF Patients 1800 1600 1400 1200 Heart failure is the most 1000 frequent diagnosis for 1,664 800 hospitalized Medicare 6X 1,2 600 patients in the US 400 200 272 0 Non-Heart Failure Heart Failure 1. Milliman Analysis of Medicare 5% Sample 2011-2012 (2012 index year, 2011 look back year) 2. Milliman Analysis of Medicare 5% Sample (2014 index year, 2013 look back year) and Office of the Actuary 2016 Board of Trustees Report. The costs only include Part A & B costs O V E R V I E W C A R D I A C C A N D I D A T E S S K E L E T A L C A N D I D A TE S C O R P O R A TE P R OF I L E 16 Annual Inpatient Admits per 1,000
Significant Unmet Need in HFrEF Proprietary market research suggests need for novel therapy Market research Drugs that Drugs that Disease Drugs that do Drugs that suggests need do not affect enhance cardiac modifying not affect BP increase QoL for novel therapy renal function performance therapies Physicians say newly Most physicians BP often limiting factor Need drugs that target Need drugs that safely Patient management approved therapies recognize negative effect for up titration and novel/more specific enhance contractility will improve with drugs have prolonged survival, therapies such as therapy initiation molecular targets that increase QoL Increased EF most decreased hospital aldosterone antagonists Need efficacious drugs Need targets other than frequently mentioned Patient QoL decreases visits, but still see need have on renal function that do not result in the neurohormonal desired measure as they lose the ability to for other therapies hypotension pathway; perform daily tasks that reduce mortality O V E R V I E W C A R D I A C C A N D I D A T E S S K E L E T A L C A N D I D A TE S C O R P O R A TE P R OF I L E 17Significant Unmet Need in HFrEF Proprietary market research suggests need for novel therapy Market research Drugs that Drugs that Disease Drugs that do Drugs that suggests need do not affect enhance cardiac modifying not affect BP increase QoL for novel therapy renal function performance therapies Physicians say newly Most physicians BP often limiting factor Need drugs that target Need drugs that safely Patient management approved therapies recognize negative effect for up titration and novel/more specific enhance contractility will improve with drugs have prolonged survival, therapies such as therapy initiation molecular targets that increase QoL Increased EF most decreased hospital aldosterone antagonists Need efficacious drugs Need targets other than frequently mentioned Patient QoL decreases visits, but still see need have on renal function that do not result in the neurohormonal desired measure as they lose the ability to for other therapies hypotension pathway; perform daily tasks that reduce mortality O V E R V I E W C A R D I A C C A N D I D A T E S S K E L E T A L C A N D I D A TE S C O R P O R A TE P R OF I L E 17
Significant Unmet Need in HCM Current therapies do not target underlying disease Current medical HCM is an inherited Surgical intervention therapy does not target cardiovascular disease not permanent solution underlying disease 1 in 500 have genetic mutation Invasive therapy to reduce Indirect mechanisms of action with septal thickness is effective systemic side effects 1 in 3200 have HCM Surgical myectomy or Variable efficacy, often inadequate Subset of patients have percutaneous ablation progressive symptoms, atrial fibrillation, stroke, sudden death O V E R V I E W C A R D I A C C A N D I D A T E S S K E L E T A L C A N D I D A TE S C O R P O R A TE P R OF I L E 18Significant Unmet Need in HCM Current therapies do not target underlying disease Current medical HCM is an inherited Surgical intervention therapy does not target cardiovascular disease not permanent solution underlying disease 1 in 500 have genetic mutation Invasive therapy to reduce Indirect mechanisms of action with septal thickness is effective systemic side effects 1 in 3200 have HCM Surgical myectomy or Variable efficacy, often inadequate Subset of patients have percutaneous ablation progressive symptoms, atrial fibrillation, stroke, sudden death O V E R V I E W C A R D I A C C A N D I D A T E S S K E L E T A L C A N D I D A TE S C O R P O R A TE P R OF I L E 18
Sarcomere Directed Drug Development Cardiac muscle The sarcomere is a molecular structure found in skeletal and cardiac muscle that enables cardiac myocytes to contract and generate force Troponin Activate Activate Inhibit Inhibit AMG 594 Omecamtiv CK-274 CK-271 (Cardiac) Mecarbil (Cardiac) (Cardiac) Myosin (Cardiac) Tropomyosin Actin Calcium Thin filament ATP Myosin Myosin head lever arm Thick filament 19 19Sarcomere Directed Drug Development Cardiac muscle The sarcomere is a molecular structure found in skeletal and cardiac muscle that enables cardiac myocytes to contract and generate force Troponin Activate Activate Inhibit Inhibit AMG 594 Omecamtiv CK-274 CK-271 (Cardiac) Mecarbil (Cardiac) (Cardiac) Myosin (Cardiac) Tropomyosin Actin Calcium Thin filament ATP Myosin Myosin head lever arm Thick filament 19 19
Omecamtiv Mecarbil: Novel Mechanism Approach O V E R V I E W C A R D I A C C A N D I D A T E S S K E L E T A L C A N D I D A TE S C O R P O R A TE P R OF I L E 20Omecamtiv Mecarbil: Novel Mechanism Approach O V E R V I E W C A R D I A C C A N D I D A T E S S K E L E T A L C A N D I D A TE S C O R P O R A TE P R OF I L E 20
Omecamtiv Mecarbil: Pivotal Phase 3 Results Q4 2020 11 Phase 1 studies with over 300 patients, 7 Phase 2 trials with over 1,400 patients Initiate Initiate Initiate Initiate METEORIC-HF Amgen Amgen Option First Cardiac First CTA/ CK-1827452 GALACTIC-HF COSMIC-HF ATOMIC-AHF Exercises Agreement Sarcomere Screen Regulatory Filing First Synthesized Option Phase 3 Phase 2 First POC Isolated CK-1827452 Phase 1 CY 1121 Hearts and in Candidate CY 1111 vivo Selection O V E R V I E W C A R D I A C C A N D I D A T E S S K E L E T A L C A N D I D A TE S C O R P O R A TE P R OF I L E 21Omecamtiv Mecarbil: Pivotal Phase 3 Results Q4 2020 11 Phase 1 studies with over 300 patients, 7 Phase 2 trials with over 1,400 patients Initiate Initiate Initiate Initiate METEORIC-HF Amgen Amgen Option First Cardiac First CTA/ CK-1827452 GALACTIC-HF COSMIC-HF ATOMIC-AHF Exercises Agreement Sarcomere Screen Regulatory Filing First Synthesized Option Phase 3 Phase 2 First POC Isolated CK-1827452 Phase 1 CY 1121 Hearts and in Candidate CY 1111 vivo Selection O V E R V I E W C A R D I A C C A N D I D A T E S S K E L E T A L C A N D I D A TE S C O R P O R A TE P R OF I L E 21
What Did We Learn from COSMIC-HF? Phase 2 clinical trial of omecamtiv mecarbil • First demonstration of the effectiveness of PK- guided dose titration to prevent excessive exposures to omecamtiv mecarbil • Demonstrated improvement in several different measures that predict improved prognosis • Decreased left ventricular volumes • Decreased NT-proBNP • Decreased heart rate • Demonstrated favorable tolerability over 20 weeks of treatment O V E R V I E W C A R D I A C C A N D I D A T E S S K E L E T A L C A N D I D A TE S C O R P O R A TE P R OF I L E 22What Did We Learn from COSMIC-HF? Phase 2 clinical trial of omecamtiv mecarbil • First demonstration of the effectiveness of PK- guided dose titration to prevent excessive exposures to omecamtiv mecarbil • Demonstrated improvement in several different measures that predict improved prognosis • Decreased left ventricular volumes • Decreased NT-proBNP • Decreased heart rate • Demonstrated favorable tolerability over 20 weeks of treatment O V E R V I E W C A R D I A C C A N D I D A T E S S K E L E T A L C A N D I D A TE S C O R P O R A TE P R OF I L E 22
Dose-Dependent Increases in Cardiac Performance Pharmacodynamic results from COSMIC-HF SET Stroke Volume 8 40 p = 0.004 p = 0.022 p = 0.001 p < 0.001 35 6 30 4 25 2 20 15 0 10 -2 5 -4 0 Placebo 25 mg All PK Titration Placebo 25 mg All PK Titration LVFS LVEF 7.0 5 p = 0.025 p = 0.063 p = 0.017 p = 0.013 4 5.0 3 3.0 2 1.0 1 0 -1.0 Placebo 25 mg All PK Titration Placebo 25 mg All PK Titration LVEF, left ventricular ejection fraction; LVFS, left ventricular fractional shortening; SE, standard error; SET, systolic ejection time ; all p values are nominal without multiplicity adjustment. O V E R V I E W C A R D I A C C A N D I D A T E S S K E L E T A L C A N D I D A TE S C O R P O R A TE P R OF I L E 23 LS Mean (SE) Change (%) LS Mean (SE) Change (msec) LS Mean (SE) Change (%) LS Mean (SE) Change (mL)Dose-Dependent Increases in Cardiac Performance Pharmacodynamic results from COSMIC-HF SET Stroke Volume 8 40 p = 0.004 p = 0.022 p = 0.001 p < 0.001 35 6 30 4 25 2 20 15 0 10 -2 5 -4 0 Placebo 25 mg All PK Titration Placebo 25 mg All PK Titration LVFS LVEF 7.0 5 p = 0.025 p = 0.063 p = 0.017 p = 0.013 4 5.0 3 3.0 2 1.0 1 0 -1.0 Placebo 25 mg All PK Titration Placebo 25 mg All PK Titration LVEF, left ventricular ejection fraction; LVFS, left ventricular fractional shortening; SE, standard error; SET, systolic ejection time ; all p values are nominal without multiplicity adjustment. O V E R V I E W C A R D I A C C A N D I D A T E S S K E L E T A L C A N D I D A TE S C O R P O R A TE P R OF I L E 23 LS Mean (SE) Change (%) LS Mean (SE) Change (msec) LS Mean (SE) Change (%) LS Mean (SE) Change (mL)
Decreases in Physiology & Cardiac Risk Reductions in heart volume, oxygen demand & wall stress in COSMIC-HF LVEDV LVESV 10 0 5 -5 0 -10 -5 -10 -15 p = 0.062 p = 0.021 -15 -20 p = 0.019 p = 0.005 -20 -25 Placebo 25 mg All PK Titration Placebo 25 mg All PK Titration Heart Rate NT-proBNP 0 0 -1 P = 0.14 -300 -2 P = 0.007 -600 P = 0.007 -3 P = 0.087 -4 -900 P < 0.0001 P = 0.007 -5 -1200 4 8 12 16 20 Baseline 4 8 12 16 20 Baseline Weeks 2715 ± 258 pg/mL Weeks LVESV left ventricular end systolic volume; LVEDV left ventricular end diastolic volume All p values are nominal without multiplicity adjustment O V E R V I E W C A R D I A C C A N D I D A T E S S K E L E T A L C A N D I D A TE S C O R P O R A TE P R OF I L E 24 LS Mean (SE) Change (bpm) LS Mean (SE) Change (mL) LS Mean (SE) Change (pg/mL) LS Mean (SE) Change (mL)Decreases in Physiology & Cardiac Risk Reductions in heart volume, oxygen demand & wall stress in COSMIC-HF LVEDV LVESV 10 0 5 -5 0 -10 -5 -10 -15 p = 0.062 p = 0.021 -15 -20 p = 0.019 p = 0.005 -20 -25 Placebo 25 mg All PK Titration Placebo 25 mg All PK Titration Heart Rate NT-proBNP 0 0 -1 P = 0.14 -300 -2 P = 0.007 -600 P = 0.007 -3 P = 0.087 -4 -900 P < 0.0001 P = 0.007 -5 -1200 4 8 12 16 20 Baseline 4 8 12 16 20 Baseline Weeks 2715 ± 258 pg/mL Weeks LVESV left ventricular end systolic volume; LVEDV left ventricular end diastolic volume All p values are nominal without multiplicity adjustment O V E R V I E W C A R D I A C C A N D I D A T E S S K E L E T A L C A N D I D A TE S C O R P O R A TE P R OF I L E 24 LS Mean (SE) Change (bpm) LS Mean (SE) Change (mL) LS Mean (SE) Change (pg/mL) LS Mean (SE) Change (mL)
Neutral or Improved Measures of Diastolic Function Improved systolic function with no negative impact on diastolic function E/e’ IVRT 1 10 p<0.0001 p<0.0001 0 5 p=0.6718 0 -1 p=0.1355 -5 -2 Placebo 25 mg Fixed Dose PK Titration Placebo 25 mg Fixed Dose PK Titration TR Velocity Diastolic Filling Time 10 20 10 0 0 -10 -10 p=0.9767 p=0.877 -20 -20 p=0.221 p=0.0055 -30 -30 Placebo PK Titration Placebo PK Titration 25 mg Fixed Dose 25 mg Fixed Dose IVRT=isovolumic relaxation time TR=tricuspid regurgitation O V E R V I E W C A R D I A C C A N D I D A T E S S K E L E T A L C A N D I D A TE S C O R P O R A TE P R OF I L E 25 Change in TR velocity (cm/s) Change in E/e' ratio Change in IVRT (ms)Neutral or Improved Measures of Diastolic Function Improved systolic function with no negative impact on diastolic function E/e’ IVRT 1 10 p<0.0001 p<0.0001 0 5 p=0.6718 0 -1 p=0.1355 -5 -2 Placebo 25 mg Fixed Dose PK Titration Placebo 25 mg Fixed Dose PK Titration TR Velocity Diastolic Filling Time 10 20 10 0 0 -10 -10 p=0.9767 p=0.877 -20 -20 p=0.221 p=0.0055 -30 -30 Placebo PK Titration Placebo PK Titration 25 mg Fixed Dose 25 mg Fixed Dose IVRT=isovolumic relaxation time TR=tricuspid regurgitation O V E R V I E W C A R D I A C C A N D I D A T E S S K E L E T A L C A N D I D A TE S C O R P O R A TE P R OF I L E 25 Change in TR velocity (cm/s) Change in E/e' ratio Change in IVRT (ms)
Improvements in Symptoms Change from Baseline in KCCQ Total Symptoms Score at Week 20 4.9-point improvement p= 0.03 14 12 10 8 6 4 2 0 Placebo OM 25 mg BID PK-titration Change from Baseline in KCCQ Subdomain Scores at Week 20 Symptom Frequency Symptom Burden 12 18 16 10 14 8 12 10 6 8 4 6 4 2 2 0 0 Placebo OM 25 mg BID PK-titration Placebo OM 25 mg BID PK-titration CI: confidence interval O V E R V I E W C A R D I A C C A N D I D A T E S S K E L E T A L C A N D I D A TE S C O R P O R A TE P R OF I L E 26 Mean (95% CI) Change Mean (95% CI) Change Mean (95% CI) ChangeImprovements in Symptoms Change from Baseline in KCCQ Total Symptoms Score at Week 20 4.9-point improvement p= 0.03 14 12 10 8 6 4 2 0 Placebo OM 25 mg BID PK-titration Change from Baseline in KCCQ Subdomain Scores at Week 20 Symptom Frequency Symptom Burden 12 18 16 10 14 8 12 10 6 8 4 6 4 2 2 0 0 Placebo OM 25 mg BID PK-titration Placebo OM 25 mg BID PK-titration CI: confidence interval O V E R V I E W C A R D I A C C A N D I D A T E S S K E L E T A L C A N D I D A TE S C O R P O R A TE P R OF I L E 26 Mean (95% CI) Change Mean (95% CI) Change Mean (95% CI) Change
Troponins: Small Increases, Unrelated to Exposures to Omecamtiv Mecarbil COSMIC-HF • Baseline troponin I levels were above the diagnostic limit for myocardial infarction (0.04 ng/mL) for ~25% in COSMIC-HF • Events of increased troponin I (n=278 across all treatment groups) were independently adjudicated and none Troponin I Levels in COSMIC-HF (ng/mL) were determined to be myocardial Placebo 25 mg BID All PK Titration All OM ischemia or Median at Baseline 0.025 0.022 0.022 0.022 1 infarction. (Q1, Q3) (0.016, 0.041) (0.016, 0.039) (0.016, 0.042) 0.016, 0.040 Median Change from 0.000 0.001 0.006 0.004 Baseline to Week 20 (-0.007, 0.004) (0.000, 0.012) (0.000, 0.024) (0.000, 0.019) (Q1, Q3) 1. Teerlink, et al. The Lancet 2016; 2895-2903 O V E R V I E W C A R D I A C C A N D I D A T E S S K E L E T A L C A N D I D A TE S C O R P O R A TE P R OF I L E 27Troponins: Small Increases, Unrelated to Exposures to Omecamtiv Mecarbil COSMIC-HF • Baseline troponin I levels were above the diagnostic limit for myocardial infarction (0.04 ng/mL) for ~25% in COSMIC-HF • Events of increased troponin I (n=278 across all treatment groups) were independently adjudicated and none Troponin I Levels in COSMIC-HF (ng/mL) were determined to be myocardial Placebo 25 mg BID All PK Titration All OM ischemia or Median at Baseline 0.025 0.022 0.022 0.022 1 infarction. (Q1, Q3) (0.016, 0.041) (0.016, 0.039) (0.016, 0.042) 0.016, 0.040 Median Change from 0.000 0.001 0.006 0.004 Baseline to Week 20 (-0.007, 0.004) (0.000, 0.012) (0.000, 0.024) (0.000, 0.019) (Q1, Q3) 1. Teerlink, et al. The Lancet 2016; 2895-2903 O V E R V I E W C A R D I A C C A N D I D A T E S S K E L E T A L C A N D I D A TE S C O R P O R A TE P R OF I L E 27
Prognostic Implications: NT-proBNP and Remodeling Studies demonstrate correlation with cardiovascular outcomes Patients in PARADIGM-HF who had significant reductions in NT-proBNP had lower rates of CV death or heart 1 failure hospitalization Meta-analysis of drug/device therapies demonstrated association between LV remodeling and longer-term effects on 2 mortality in patients with LVD 1. Zile et al. JACC 2016; 68(22); 2425-2436 2. Kramer et al. JACC 2010;56(5):392-406 O V E R V I E W C A R D I A C C A N D I D A T E S S K E L E T A L C A N D I D A TE S C O R P O R A TE P R OF I L E 28Prognostic Implications: NT-proBNP and Remodeling Studies demonstrate correlation with cardiovascular outcomes Patients in PARADIGM-HF who had significant reductions in NT-proBNP had lower rates of CV death or heart 1 failure hospitalization Meta-analysis of drug/device therapies demonstrated association between LV remodeling and longer-term effects on 2 mortality in patients with LVD 1. Zile et al. JACC 2016; 68(22); 2425-2436 2. Kramer et al. JACC 2010;56(5):392-406 O V E R V I E W C A R D I A C C A N D I D A T E S S K E L E T A L C A N D I D A TE S C O R P O R A TE P R OF I L E 28
Pivotal Phase 3 Trial Completed Enrollment GALACTIC-HF continuing following second planned interim analysis Topline results expected in Q4 2020 Overview Key Design Points Enrolled 8,256 patients at ~1,000 sites in 35 countries • Dose optimization based on trough concentration of omecamtiv mecarbil at 2 weeks and 6 weeks Primary Endpoint • High risk patients enrolled from inpatient and outpatient settings Composite of time to cardiovascular (CV) death or first HF event*, whichever occurs first • Designed to provide 90% statistical power to assess risk of CV death Secondary Endpoints • Time to CV death • Change in Kansas City Cardiomyopathy Questionnaire Total Symptoms Score (KCCQ TSS) from baseline to Week 24 • Time to first HF hospitalization • Time to all-cause death *An HF event defined as the presentation of the subject for an urgent, unscheduled clinic/office/ED visit, or hospital admission, with a primary diagnosis of HF, where the patient exhibits new or worsening symptoms of HF on presentation, has objective evidence of new or worsening HF, and receives initiation or intensification of treatment specifically for HF (Hicks et al, 2015). Changes to oral diuretic therapy do not qualify as initiation or intensification of treatment. O V E R V I E W C A R D I A C C A N D I D A T E S S K E L E T A L C A N D I D A TE S C O R P O R A TE P R OF I L E 29Pivotal Phase 3 Trial Completed Enrollment GALACTIC-HF continuing following second planned interim analysis Topline results expected in Q4 2020 Overview Key Design Points Enrolled 8,256 patients at ~1,000 sites in 35 countries • Dose optimization based on trough concentration of omecamtiv mecarbil at 2 weeks and 6 weeks Primary Endpoint • High risk patients enrolled from inpatient and outpatient settings Composite of time to cardiovascular (CV) death or first HF event*, whichever occurs first • Designed to provide 90% statistical power to assess risk of CV death Secondary Endpoints • Time to CV death • Change in Kansas City Cardiomyopathy Questionnaire Total Symptoms Score (KCCQ TSS) from baseline to Week 24 • Time to first HF hospitalization • Time to all-cause death *An HF event defined as the presentation of the subject for an urgent, unscheduled clinic/office/ED visit, or hospital admission, with a primary diagnosis of HF, where the patient exhibits new or worsening symptoms of HF on presentation, has objective evidence of new or worsening HF, and receives initiation or intensification of treatment specifically for HF (Hicks et al, 2015). Changes to oral diuretic therapy do not qualify as initiation or intensification of treatment. O V E R V I E W C A R D I A C C A N D I D A T E S S K E L E T A L C A N D I D A TE S C O R P O R A TE P R OF I L E 29
Clinical Trial Overview Chronic HFrEF patients Omecamtiv mecarbil + SoC Starting dose: 25mg PO BID currently hospitalized for a primary reason of HF or with history of hospitalization or ER/ED admission for a primary Placebo + SoC reason of HF within 1 year Follow the same study procedures as OM group to ensure blinding Study Visits D1 W2 W4 W6 W8 W12 W24 W36 W48 Q16W PK assessment for dose adjustment PK assessment O V E R V I E W C A R D I A C C A N D I D A T E S S K E L E T A L C A N D I D A TE S C O R P O R A TE P R OF I L E 30 Screening Randomization 1:1 Stratified by Patient Subsets and Region EOSClinical Trial Overview Chronic HFrEF patients Omecamtiv mecarbil + SoC Starting dose: 25mg PO BID currently hospitalized for a primary reason of HF or with history of hospitalization or ER/ED admission for a primary Placebo + SoC reason of HF within 1 year Follow the same study procedures as OM group to ensure blinding Study Visits D1 W2 W4 W6 W8 W12 W24 W36 W48 Q16W PK assessment for dose adjustment PK assessment O V E R V I E W C A R D I A C C A N D I D A T E S S K E L E T A L C A N D I D A TE S C O R P O R A TE P R OF I L E 30 Screening Randomization 1:1 Stratified by Patient Subsets and Region EOS
GALACTIC-HF: Design Paper & Interim Analyses • Passed first interim analysis: Q1 2019 • Assessed futility only (HR>1.0) • Triggered at 1/3 of target 1,590 deaths • Passed second interim analysis: Q1 2020 • Assessed futility & superiority • Triggered at 2/3 of target 1,590 deaths • Superiority: p-value for efficacy <0.0005 (one-sided alpha) O V E R V I E W C A R D I A C C A N D I D A T E S S K E L E T A L C A N D I D A TE S C O R P O R A TE P R OF I L E 31GALACTIC-HF: Design Paper & Interim Analyses • Passed first interim analysis: Q1 2019 • Assessed futility only (HR>1.0) • Triggered at 1/3 of target 1,590 deaths • Passed second interim analysis: Q1 2020 • Assessed futility & superiority • Triggered at 2/3 of target 1,590 deaths • Superiority: p-value for efficacy <0.0005 (one-sided alpha) O V E R V I E W C A R D I A C C A N D I D A T E S S K E L E T A L C A N D I D A TE S C O R P O R A TE P R OF I L E 31
Baseline Characteristics: High Risk Population Overall Inpatient Outpatient (N=8,256) (N=2,083) (N=6,173) • 8,256 patients enrolled in 35 Time from most recent HF hospitalization/ 2 (1-5) - 3 (2-6) ED visit (months), median (Q1-Q3) countries Age (years), mean (SD) 65 (11) 65 (11) 64 (11) • Population at high risk for Male, % 79 80 78 White, % cardiovascular events despite being 78 82 76 LVEF (%), mean (SD) 27 (6) 27 (6) 27 (6) well-treated on standard of care NYHA Class II/III/IV, % 53/ 44/ 3 37/ 57/ 6 59/ 39/ 2 NT-proBNP (pg/mL), median (Q1-Q3) 1998 (990-4078) 2509 (1240-5133) 1884 (923-3772) • Inpatient population: 25% Ischemic Heart Disease Etiology, % 55 56 54 KCCQ Total Symptom Score, mean (SD) • Time from most recent HF 66 (25) 53 (25) 71 (23) Atrial Fibrillation or Flutter History, % 42 48 40 hospitalization/ED visit (months), Chronic Kidney Disease, % 36 39 35 median (Q1-Q3): 2 (1-5) 2 eGFR (mL/min/1.73m ), median (Q1-Q3) 59 (44-74) 54 (41-70) 60 (45-75) SBP (mmHg), mean (SD) 117 (15) 114 (14) 117 (16) • NT-proBNP, median (Q1–Q3): 1,998 ACEi, ARB or ARNi, % 87 83 88 pg/mL (990-4,078) ARNi (ENTRESTO®) % 19 14 19 Beta Blocker, % 94 93 95 • LVEF, mean: 27% MRA, % 77 81 76 Diuretics other than MRAs, % • ENTRESTO® use: 19% 90 92 89 Digitalis Glycosides, % 17 17 17 SGLT2 Inhibitors, % 3 3 3 O V E R V I E W C A R D I A C C A N D I D A T E S S K E L E T A L C A N D I D A TE S C O R P O R A TE P R OF I L E 32Baseline Characteristics: High Risk Population Overall Inpatient Outpatient (N=8,256) (N=2,083) (N=6,173) • 8,256 patients enrolled in 35 Time from most recent HF hospitalization/ 2 (1-5) - 3 (2-6) ED visit (months), median (Q1-Q3) countries Age (years), mean (SD) 65 (11) 65 (11) 64 (11) • Population at high risk for Male, % 79 80 78 White, % cardiovascular events despite being 78 82 76 LVEF (%), mean (SD) 27 (6) 27 (6) 27 (6) well-treated on standard of care NYHA Class II/III/IV, % 53/ 44/ 3 37/ 57/ 6 59/ 39/ 2 NT-proBNP (pg/mL), median (Q1-Q3) 1998 (990-4078) 2509 (1240-5133) 1884 (923-3772) • Inpatient population: 25% Ischemic Heart Disease Etiology, % 55 56 54 KCCQ Total Symptom Score, mean (SD) • Time from most recent HF 66 (25) 53 (25) 71 (23) Atrial Fibrillation or Flutter History, % 42 48 40 hospitalization/ED visit (months), Chronic Kidney Disease, % 36 39 35 median (Q1-Q3): 2 (1-5) 2 eGFR (mL/min/1.73m ), median (Q1-Q3) 59 (44-74) 54 (41-70) 60 (45-75) SBP (mmHg), mean (SD) 117 (15) 114 (14) 117 (16) • NT-proBNP, median (Q1–Q3): 1,998 ACEi, ARB or ARNi, % 87 83 88 pg/mL (990-4,078) ARNi (ENTRESTO®) % 19 14 19 Beta Blocker, % 94 93 95 • LVEF, mean: 27% MRA, % 77 81 76 Diuretics other than MRAs, % • ENTRESTO® use: 19% 90 92 89 Digitalis Glycosides, % 17 17 17 SGLT2 Inhibitors, % 3 3 3 O V E R V I E W C A R D I A C C A N D I D A T E S S K E L E T A L C A N D I D A TE S C O R P O R A TE P R OF I L E 32
Comparing Patients in Large Heart Failure Trials Highest risk patients in VICTORIA; lower risk in PARADIGM-HF, DAPA-HF GALACTIC-HF VICTORIA PARADIGM-HF DAPA-HF (N=8,256) (N=5,050) (N=8,339) (N=4,744) Age (y, mean (SD)) 65 (11) 67.3 (12.2) 63.8 (11.4) 66 (11) Race White 6,358 (77.0%) 3,239 (64.1%) 5,544 (65.7%) 3,333 (70.2%) Black or African American 561 (6.7%) 249 (4.9%) 428 (5.1%) 226 (4.7%) Asian 710 (8.6%) 1,132 (22.4%) 1,509 (17.9%) 1,109 (23.3%) Other 627 (7.6%) 430 (8.5%) 918 (11.0%) 76 (1.6%) Geographic Region Eastern Europe 2,705 (32.7%) 1,694 (33.5%) 2,826 (33.5%) 1,604 (33.8%) Western Europe 1,921 (23.3%) 889 (17.6%) 2,051 (24.3%) 550 (11.6%) Asia Pacific 670 (8.1%) 1,183 (23.4%) 1,487 (17.6%) 1,096 (23.1%) Latin and South America 1,575 (19.1%) 724 (14.3%) 1,433 (17.0%) 816 (17.2%) North America 1,386 (16.8%) 560 (11.1%) 602 (7.1%) 678 (14.3%) Ejection fraction at screening (% mean (SD)) 26.6 (6.3) 28.9 (8.3) 29.5 (6.2) 31.1 (6.8) Concomitant Medications ACE-I or ARB 5,803 (70.3%) 3,700 (73.4%) 8,339 (100%) 3,986 (83.6%) Beta blocker 7,763 (94.0%) 4,691 (93.1%) 7,811 (93.6%) 4,558 (96.0%) MRA 6,363 (77.1%) 3,545 (70.3%) 4,671 (55.3%) 3,370 (71.0%) ARNI sacubitril/valsartan 1.595 (19.3%) 731 (14.5%) - 508 (10.7%) th th NT-proBNP at Screening (pg/ml, median (25 , 75 )) 1,998 (990-4078) 2,816 (1556-5314) 1,608 (886-3,221) 1,428 (857-2,649) NYHA Class at Baseline Class II 4,376 (53.0%) 2,975 (59.0%) 5,919 (70.1%) 3,203 (67.5%) Class III 3,633 (44.0%) 2,003 (39.7%) 2,018 (23.9%) 1,498 (31.6%) Class IV 248 (3.0%) 66 (1.3%) 60 (0.7%) 43 (0.9%) O V E R V I E W C A R D I A C C A N D I D A T E S S K E L E T A L C A N D I D A TE S C O R P O R A TE P R OF I L E 33Comparing Patients in Large Heart Failure Trials Highest risk patients in VICTORIA; lower risk in PARADIGM-HF, DAPA-HF GALACTIC-HF VICTORIA PARADIGM-HF DAPA-HF (N=8,256) (N=5,050) (N=8,339) (N=4,744) Age (y, mean (SD)) 65 (11) 67.3 (12.2) 63.8 (11.4) 66 (11) Race White 6,358 (77.0%) 3,239 (64.1%) 5,544 (65.7%) 3,333 (70.2%) Black or African American 561 (6.7%) 249 (4.9%) 428 (5.1%) 226 (4.7%) Asian 710 (8.6%) 1,132 (22.4%) 1,509 (17.9%) 1,109 (23.3%) Other 627 (7.6%) 430 (8.5%) 918 (11.0%) 76 (1.6%) Geographic Region Eastern Europe 2,705 (32.7%) 1,694 (33.5%) 2,826 (33.5%) 1,604 (33.8%) Western Europe 1,921 (23.3%) 889 (17.6%) 2,051 (24.3%) 550 (11.6%) Asia Pacific 670 (8.1%) 1,183 (23.4%) 1,487 (17.6%) 1,096 (23.1%) Latin and South America 1,575 (19.1%) 724 (14.3%) 1,433 (17.0%) 816 (17.2%) North America 1,386 (16.8%) 560 (11.1%) 602 (7.1%) 678 (14.3%) Ejection fraction at screening (% mean (SD)) 26.6 (6.3) 28.9 (8.3) 29.5 (6.2) 31.1 (6.8) Concomitant Medications ACE-I or ARB 5,803 (70.3%) 3,700 (73.4%) 8,339 (100%) 3,986 (83.6%) Beta blocker 7,763 (94.0%) 4,691 (93.1%) 7,811 (93.6%) 4,558 (96.0%) MRA 6,363 (77.1%) 3,545 (70.3%) 4,671 (55.3%) 3,370 (71.0%) ARNI sacubitril/valsartan 1.595 (19.3%) 731 (14.5%) - 508 (10.7%) th th NT-proBNP at Screening (pg/ml, median (25 , 75 )) 1,998 (990-4078) 2,816 (1556-5314) 1,608 (886-3,221) 1,428 (857-2,649) NYHA Class at Baseline Class II 4,376 (53.0%) 2,975 (59.0%) 5,919 (70.1%) 3,203 (67.5%) Class III 3,633 (44.0%) 2,003 (39.7%) 2,018 (23.9%) 1,498 (31.6%) Class IV 248 (3.0%) 66 (1.3%) 60 (0.7%) 43 (0.9%) O V E R V I E W C A R D I A C C A N D I D A T E S S K E L E T A L C A N D I D A TE S C O R P O R A TE P R OF I L E 33
Second Phase 3 Clinical Trial Underway Investigating effect of omecamtiv mecarbil on exercise tolerance Trial enrolling patients in 9 countries in North America and Europe Primary Endpoint Study Plan Key Design Points Change in peak VO2 on CPET from baseline to • Designed to enroll approximately Total Countries 9 Week 20 Planned 270 patients Second Endpoints Active • 90% power 4 Countries • Patients must have LVEF ≤35 • Change in total workload during CPET from Total Sites percent, be NYHA heart failure baseline to Week 20 92 Planned class II or III, and have reduced • Change in ventilatory efficiency (VE/VCO2 slope) exercise capacity during CPET from baseline to Week 20 Activated 69 Sites • Change in average daily activity units measured • Patients randomized 2:1 to over 2 weeks from baseline to Week 18-20 by omecamtiv mecarbil Total Patients accelerometry 270 Planned VO2 = Oxygen Uptake; CPET = Cardio-Pulmonary Exercise Testing; VE = Ventilatory Efficiency O V E R V I E W C A R D I A C C A N D I D A T E S S K E L E T A L C A N D I D A TE S C O R P O R A TE P R OF I L E 34Second Phase 3 Clinical Trial Underway Investigating effect of omecamtiv mecarbil on exercise tolerance Trial enrolling patients in 9 countries in North America and Europe Primary Endpoint Study Plan Key Design Points Change in peak VO2 on CPET from baseline to • Designed to enroll approximately Total Countries 9 Week 20 Planned 270 patients Second Endpoints Active • 90% power 4 Countries • Patients must have LVEF ≤35 • Change in total workload during CPET from Total Sites percent, be NYHA heart failure baseline to Week 20 92 Planned class II or III, and have reduced • Change in ventilatory efficiency (VE/VCO2 slope) exercise capacity during CPET from baseline to Week 20 Activated 69 Sites • Change in average daily activity units measured • Patients randomized 2:1 to over 2 weeks from baseline to Week 18-20 by omecamtiv mecarbil Total Patients accelerometry 270 Planned VO2 = Oxygen Uptake; CPET = Cardio-Pulmonary Exercise Testing; VE = Ventilatory Efficiency O V E R V I E W C A R D I A C C A N D I D A T E S S K E L E T A L C A N D I D A TE S C O R P O R A TE P R OF I L E 34
Clinical Trial Overview Omecamtiv mecarbil + SoC Starting dose 25mg BID; titrated by PK to 25, 37.5 or 50 mg BID Subjects with chronic HFrEF and reduced exercise capacity Placebo + SoC “Titrated” to maintain study blind Study Visits Screen W-2 D1 W2 W4 W6 W8 W14 W20 W24 OM Concentration Dose Adjustment CPET Echocardiogram* Actigraphy *Screening echocardiogram is not required if an appropriate LVEF assessment has been performed within one year O V E R V I E W C A R D I A C C A N D I D A T E S S K E L E T A L C A N D I D A TE S C O R P O R A TE P R OF I L E 35 Screening Randomized 2:1 (omecamtiv mecarbil: placebo) End of StudyClinical Trial Overview Omecamtiv mecarbil + SoC Starting dose 25mg BID; titrated by PK to 25, 37.5 or 50 mg BID Subjects with chronic HFrEF and reduced exercise capacity Placebo + SoC “Titrated” to maintain study blind Study Visits Screen W-2 D1 W2 W4 W6 W8 W14 W20 W24 OM Concentration Dose Adjustment CPET Echocardiogram* Actigraphy *Screening echocardiogram is not required if an appropriate LVEF assessment has been performed within one year O V E R V I E W C A R D I A C C A N D I D A T E S S K E L E T A L C A N D I D A TE S C O R P O R A TE P R OF I L E 35 Screening Randomized 2:1 (omecamtiv mecarbil: placebo) End of Study
Commercial Opportunity for New Heart Failure Therapy $1.7B sold in 2019; Q1 2020 sales increased 62% year over year ® Entresto Global Product Sales (M) 1.7bn US Ex-US 569 518 1.0bn 430 421 357 318 507m 271 239 200 185 128 110 84 Q1 Q2 Q3 Q4 Q1 Q2 Q3 Q4 Q1 Q2 Q3 Q4 Q1 2017 2018 2019 2020 *As with all products in Phase 3, the product profile achieved by omecamtiv mecarbil in GALACTIC-HF is required to provide a better understanding of the expected revenue. Source: Novartis public quarterly results presentations O V E R V I E W C A R D I A C C A N D I D A T E S S K E L E T A L C A N D I D A TE S C O R P O R A TE P R OF I L E 36Commercial Opportunity for New Heart Failure Therapy $1.7B sold in 2019; Q1 2020 sales increased 62% year over year ® Entresto Global Product Sales (M) 1.7bn US Ex-US 569 518 1.0bn 430 421 357 318 507m 271 239 200 185 128 110 84 Q1 Q2 Q3 Q4 Q1 Q2 Q3 Q4 Q1 Q2 Q3 Q4 Q1 2017 2018 2019 2020 *As with all products in Phase 3, the product profile achieved by omecamtiv mecarbil in GALACTIC-HF is required to provide a better understanding of the expected revenue. Source: Novartis public quarterly results presentations O V E R V I E W C A R D I A C C A N D I D A T E S S K E L E T A L C A N D I D A TE S C O R P O R A TE P R OF I L E 36
Commercial Readiness for Omecamtiv Mecarbil Multiple workstreams in progress to prepare for successful commercial launch Determine areas of Cultivate advocacy Educate heart failure Assess impact for differentiation for heart failure market value proposition for HCPs patients O V E R V I E W C A R D I A C C A N D I D A T E S S K E L E T A L C A N D I D A TE S C O R P O R A TE P R OF I L E 37Commercial Readiness for Omecamtiv Mecarbil Multiple workstreams in progress to prepare for successful commercial launch Determine areas of Cultivate advocacy Educate heart failure Assess impact for differentiation for heart failure market value proposition for HCPs patients O V E R V I E W C A R D I A C C A N D I D A T E S S K E L E T A L C A N D I D A TE S C O R P O R A TE P R OF I L E 37
CK-274: Next-In-Class Cardiac Myosin Inhibitor Potential treatments for patients with HCM • Discovered by company scientists independent of collaborations • Selective allosteric inhibitor of cardiac myosin • No inhibition of smooth muscle myosin observed • Potential in vivo pharmacodynamic advantages related to distinctive binding site • Optimized to minimize potential drug-drug interactions • High oral bioavailability observed across pre-clinical species Myosin • Clear pharmacokinetic/pharmacodynamic (PK/PD) relationship observed • Shallow exposure-response relationship • Projected once daily dosing to reach steady state in patients expeditiously • Goal: Enable flexible and convenient dose optimization in humans as may contribute to its efficacy and safety profile O V E R V I E W C A R D I A C C A N D I D A T E S S K E L E T A L C A N D I D A TE S C O R P O R A TE P R OF I L E 38CK-274: Next-In-Class Cardiac Myosin Inhibitor Potential treatments for patients with HCM • Discovered by company scientists independent of collaborations • Selective allosteric inhibitor of cardiac myosin • No inhibition of smooth muscle myosin observed • Potential in vivo pharmacodynamic advantages related to distinctive binding site • Optimized to minimize potential drug-drug interactions • High oral bioavailability observed across pre-clinical species Myosin • Clear pharmacokinetic/pharmacodynamic (PK/PD) relationship observed • Shallow exposure-response relationship • Projected once daily dosing to reach steady state in patients expeditiously • Goal: Enable flexible and convenient dose optimization in humans as may contribute to its efficacy and safety profile O V E R V I E W C A R D I A C C A N D I D A T E S S K E L E T A L C A N D I D A TE S C O R P O R A TE P R OF I L E 38
SAD & MAD Results Support Progression to Phase 2 Phase 1: CK-274 was well tolerated in healthy participants, no SAEs* MAD PK: Steady-State Achieved After 14 SAD PK: Absorption and Elimination Generally Dose Days of Dosing Proportional Steady-state 600 150 attained 5 mg qd x 14d 10 mg qy x 14d 3,000 400 100 2,000 Through samples only 200 50 1,000 Last dose 0 0 0 1 3 10 25 40 50 1 3 10 25 40 50 0 2 4 6 8 10 12 14 16 18 20 Dose (mg) Dose (mg) Nominal Day *No SAEs and no clinically meaningful changes in vital signs, ECGs, or laboratory tests Data points represent mean ± standard error of the mean Cmax = maximum drug plasma concentration; AUC = area under the plasma concentration curve; SAD = single ascending dose; d = day; qd = once daily O V E R V I E W C A R D I A C C A N D I D A T E S S K E L E T A L C A N D I D A TE S C O R P O R A TE P R OF I L E 39 C (ng/mL) max AUC (ng/mL) 24 CK-274 (ng/mL)SAD & MAD Results Support Progression to Phase 2 Phase 1: CK-274 was well tolerated in healthy participants, no SAEs* MAD PK: Steady-State Achieved After 14 SAD PK: Absorption and Elimination Generally Dose Days of Dosing Proportional Steady-state 600 150 attained 5 mg qd x 14d 10 mg qy x 14d 3,000 400 100 2,000 Through samples only 200 50 1,000 Last dose 0 0 0 1 3 10 25 40 50 1 3 10 25 40 50 0 2 4 6 8 10 12 14 16 18 20 Dose (mg) Dose (mg) Nominal Day *No SAEs and no clinically meaningful changes in vital signs, ECGs, or laboratory tests Data points represent mean ± standard error of the mean Cmax = maximum drug plasma concentration; AUC = area under the plasma concentration curve; SAD = single ascending dose; d = day; qd = once daily O V E R V I E W C A R D I A C C A N D I D A T E S S K E L E T A L C A N D I D A TE S C O R P O R A TE P R OF I L E 39 C (ng/mL) max AUC (ng/mL) 24 CK-274 (ng/mL)
CY 6011: MAD Pharmacokinetic Parameters Shallow Exposure-Response Relationship Observed Half-Life of CK-274 at Steady-State Preclinically Appears to Have Translated to Humans, was ~81 hours (3.4 days) On Average May Enable Flexible Dose Optimization in Humans PK/PD Relationship of CK-274 for Ejection Fraction (LVEF) Dose (n) 5 mg (6) 7.5 mg (6) 10 mg (6) 100 C (ng/mL) 69 (23.2%) 148 (39.5% 141 (19.7%) max 80 Graphs show LVEF as a function of exposure; data t (h) 2.75 (1.5–4) 1.0 (0.5–5) 2.5 (0.5–3) max 60 points represent observed values in dogs and 40 AUC (ng•h/mL) 1,321 (23.0%) 2,518 (25.8%) 2,631 (22.8%) 24 humans. 20 Decrease in LVEF Human t (h) 86.3 (11.9) 76.9 (14.5) 79.7 (14.1) as function of 1/2 Dog exposure is 0 similar in humans and dogs. AR 4.71 4.5 4.79 0.0001 0.001 0.010 0.100 1.000 Free Plasma Concentration (µmoI/L) *Except data for tmax shown as median (minimum-maximum), and t½ shown as the arithmetic mean (standard deviation). AR (accumulation ratio) calculated as (AUC24 on Day 14 or 17)/(AUC24 on Day 1). %CV = percent coefficient of variation; Cmax = maximum plasma concentration; AUC24 = area under the plasma concentration curve; MAD = multiple ascending dose; t½ = apparent plasma terminal elimination half-life; tmax = time to maximum observed plasma concentration. O V E R V I E W C A R D I A C C A N D I D A T E S S K E L E T A L C A N D I D A TE S C O R P O R A TE P R OF I L E 40 PK Parameter, Geometric Mean (%CV)* LVEF (% of Baseline)CY 6011: MAD Pharmacokinetic Parameters Shallow Exposure-Response Relationship Observed Half-Life of CK-274 at Steady-State Preclinically Appears to Have Translated to Humans, was ~81 hours (3.4 days) On Average May Enable Flexible Dose Optimization in Humans PK/PD Relationship of CK-274 for Ejection Fraction (LVEF) Dose (n) 5 mg (6) 7.5 mg (6) 10 mg (6) 100 C (ng/mL) 69 (23.2%) 148 (39.5% 141 (19.7%) max 80 Graphs show LVEF as a function of exposure; data t (h) 2.75 (1.5–4) 1.0 (0.5–5) 2.5 (0.5–3) max 60 points represent observed values in dogs and 40 AUC (ng•h/mL) 1,321 (23.0%) 2,518 (25.8%) 2,631 (22.8%) 24 humans. 20 Decrease in LVEF Human t (h) 86.3 (11.9) 76.9 (14.5) 79.7 (14.1) as function of 1/2 Dog exposure is 0 similar in humans and dogs. AR 4.71 4.5 4.79 0.0001 0.001 0.010 0.100 1.000 Free Plasma Concentration (µmoI/L) *Except data for tmax shown as median (minimum-maximum), and t½ shown as the arithmetic mean (standard deviation). AR (accumulation ratio) calculated as (AUC24 on Day 14 or 17)/(AUC24 on Day 1). %CV = percent coefficient of variation; Cmax = maximum plasma concentration; AUC24 = area under the plasma concentration curve; MAD = multiple ascending dose; t½ = apparent plasma terminal elimination half-life; tmax = time to maximum observed plasma concentration. O V E R V I E W C A R D I A C C A N D I D A T E S S K E L E T A L C A N D I D A TE S C O R P O R A TE P R OF I L E 40 PK Parameter, Geometric Mean (%CV)* LVEF (% of Baseline)
Phase 2 Clinical Trial Design Two sequential dose-finding cohorts (optional 3rd cohort) CK-3773274 + SoC Patients with 2 symptomatic oHCM, and resting or provoked LVOT 1 gradient ≥ 50 mmHg Placebo + SoC Study Visits Screen W-1 D1 W2 W4 W6 W9 W10 W12 W14 Dose 1 Dose 3 Dose 2 IP Dosing PK Echocardiogram O V E R V I E W C A R D I A C C A N D I D A T E S S K E L E T A L C A N D I D A TE S C O R P O R A TE P R OF I L E 41 Screening Randomization End of StudyPhase 2 Clinical Trial Design Two sequential dose-finding cohorts (optional 3rd cohort) CK-3773274 + SoC Patients with 2 symptomatic oHCM, and resting or provoked LVOT 1 gradient ≥ 50 mmHg Placebo + SoC Study Visits Screen W-1 D1 W2 W4 W6 W9 W10 W12 W14 Dose 1 Dose 3 Dose 2 IP Dosing PK Echocardiogram O V E R V I E W C A R D I A C C A N D I D A T E S S K E L E T A L C A N D I D A TE S C O R P O R A TE P R OF I L E 41 Screening Randomization End of Study
CK-274: Clinical Development Plan for HCM Phase 1 Phase 2 Phase 3 Safety, PK & PD Proof of Concept, Dose Finding Pivotal Studies SAD & MAD oHCM patients oHCMpatients Healthy Placebo Controlled Exercise Endpoint (peak VO2) Volunteers Echocardiography Endpoints IND Filed NDA Safe & tolerated dose NDA: Potential for approval based on a single Improved LVOT gradient with desired PD effects Ph3 study with an exercise endpoint Extension study Long-term safety & efficacy Proof of activity in nHCM pts Pivotal study in nHCM O V E R V I E W C A R D I A C C A N D I D A T E S S K E L E T A L C A N D I D A TE S C O R P O R A TE P R OF I L E 42CK-274: Clinical Development Plan for HCM Phase 1 Phase 2 Phase 3 Safety, PK & PD Proof of Concept, Dose Finding Pivotal Studies SAD & MAD oHCM patients oHCMpatients Healthy Placebo Controlled Exercise Endpoint (peak VO2) Volunteers Echocardiography Endpoints IND Filed NDA Safe & tolerated dose NDA: Potential for approval based on a single Improved LVOT gradient with desired PD effects Ph3 study with an exercise endpoint Extension study Long-term safety & efficacy Proof of activity in nHCM pts Pivotal study in nHCM O V E R V I E W C A R D I A C C A N D I D A T E S S K E L E T A L C A N D I D A TE S C O R P O R A TE P R OF I L E 42
Obstructive HCM: Potential Phase 3 Trial Endpoints • CPET – Cardiopulmonary exercise testing • Peak VO (oxygen uptake) 2 • V /VCO (ventilatory efficiency) E 2 • OUES (oxygen uptake efficiency slope) • NYHA class • Echocardiographic parameters – LVOT gradient, LVEF, LVFS, GLS • Biomarkers – NT-proBNP, Troponins • PROs – Patient-Reported Outcomes • PROMIS scores – Dyspnea, Fatigue, Physical Function • HCM-specific instruments currently being validated O V E R V I E W C A R D I A C C A N D I D A T E S S K E L E T A L C A N D I D A TE S C O R P O R A TE P R OF I L E 43Obstructive HCM: Potential Phase 3 Trial Endpoints • CPET – Cardiopulmonary exercise testing • Peak VO (oxygen uptake) 2 • V /VCO (ventilatory efficiency) E 2 • OUES (oxygen uptake efficiency slope) • NYHA class • Echocardiographic parameters – LVOT gradient, LVEF, LVFS, GLS • Biomarkers – NT-proBNP, Troponins • PROs – Patient-Reported Outcomes • PROMIS scores – Dyspnea, Fatigue, Physical Function • HCM-specific instruments currently being validated O V E R V I E W C A R D I A C C A N D I D A T E S S K E L E T A L C A N D I D A TE S C O R P O R A TE P R OF I L E 43
Non-Obstructive HCM: Human Model of HFpEF Subgroup nHCM patients with similarities to subgroups of HFpEF patients with hypercontractility Symptoms and Pathophysiology are Similar in Both Conditions Symptoms Pathophysiology nHCM Dyspnea Increased Contractility Exercise Capacity Left Ventricular Hypertrophy Diminished Peripheral Edema Diastolic Dysfunction HFpEF Fatigue Increased LV Filling Pressure Subgroup O V E R V I E W C A R D I A C C A N D I D A T E S S K E L E T A L C A N D I D A TE S C O R P O R A TE P R OF I L E 44Non-Obstructive HCM: Human Model of HFpEF Subgroup nHCM patients with similarities to subgroups of HFpEF patients with hypercontractility Symptoms and Pathophysiology are Similar in Both Conditions Symptoms Pathophysiology nHCM Dyspnea Increased Contractility Exercise Capacity Left Ventricular Hypertrophy Diminished Peripheral Edema Diastolic Dysfunction HFpEF Fatigue Increased LV Filling Pressure Subgroup O V E R V I E W C A R D I A C C A N D I D A T E S S K E L E T A L C A N D I D A TE S C O R P O R A TE P R OF I L E 44
Novel Approach Addresses Multiple Unmet Patient Needs No FDA Approved Therapies Obstructive HCM oHCM CK-274 (Cardiac myosin Inhibitor) nHCM HFpEF Non-Obstructive HCM Heart Failure with Preserved Ejection Fraction O V E R V I E W C A R D I A C C A N D I D A T E S S K E L E T A L C A N D I D A TE S C O R P O R A TE P R OF I L E 45Novel Approach Addresses Multiple Unmet Patient Needs No FDA Approved Therapies Obstructive HCM oHCM CK-274 (Cardiac myosin Inhibitor) nHCM HFpEF Non-Obstructive HCM Heart Failure with Preserved Ejection Fraction O V E R V I E W C A R D I A C C A N D I D A T E S S K E L E T A L C A N D I D A TE S C O R P O R A TE P R OF I L E 45
CV Franchise: Building to Improve Patient Healthspan Build leading CV Leverage Successfully launch, Expand CV pipeline commercial commercial omecamtiv mecarbil, internally and Improve CV patient organization organization to bring for patients with through novel healthspan supported by CK-274 & other HFrEF partnerships Amgen collaboration molecules to market Today Tomorrow Meaningfully improve the Leverage deep leadership in cardiac muscle healthspan of CV patients with an biology, to develop and commercialize initial focus on HFrEF and HCM innovative medicines for CV disease O V E R V I E W C A R D I A C C A N D I D A T E S S K E L E T A L C A N D I D A TE S C O R P O R A TE P R OF I L E 46CV Franchise: Building to Improve Patient Healthspan Build leading CV Leverage Successfully launch, Expand CV pipeline commercial commercial omecamtiv mecarbil, internally and Improve CV patient organization organization to bring for patients with through novel healthspan supported by CK-274 & other HFrEF partnerships Amgen collaboration molecules to market Today Tomorrow Meaningfully improve the Leverage deep leadership in cardiac muscle healthspan of CV patients with an biology, to develop and commercialize initial focus on HFrEF and HCM innovative medicines for CV disease O V E R V I E W C A R D I A C C A N D I D A T E S S K E L E T A L C A N D I D A TE S C O R P O R A TE P R OF I L E 46
Building Synergistic Commercial Capabilities Building Today… To Lead Tomorrow BUILDING TODAY… Building commercial organization focused Establish Cytokinetics as a CV leader by on hospitalized CV patients and HCPs to leveraging commercial capabilities for optimize opportunity for omecamtiv mecarbil future product launches • Leverage funding from Amgen collaboration• Significant overlap between HFrEF & HCM accounts • Cultivate advocacy with CV patients and HCPs• Simultaneously gain experience in HFrEF & HCM Highest Value 6,000+ ~75% HFrEF Patients Hospitals & Hospitals and CoEs ~78% HCM Patients CoEs in US IQVIA HPD – Q3’18 – Q2’19 O V E R V I E W C A R D I A C C A N D I D A T E S S K E L E T A L C A N D I D A TE S C O R P O R A TE P R OF I L E 47Building Synergistic Commercial Capabilities Building Today… To Lead Tomorrow BUILDING TODAY… Building commercial organization focused Establish Cytokinetics as a CV leader by on hospitalized CV patients and HCPs to leveraging commercial capabilities for optimize opportunity for omecamtiv mecarbil future product launches • Leverage funding from Amgen collaboration• Significant overlap between HFrEF & HCM accounts • Cultivate advocacy with CV patients and HCPs• Simultaneously gain experience in HFrEF & HCM Highest Value 6,000+ ~75% HFrEF Patients Hospitals & Hospitals and CoEs ~78% HCM Patients CoEs in US IQVIA HPD – Q3’18 – Q2’19 O V E R V I E W C A R D I A C C A N D I D A T E S S K E L E T A L C A N D I D A TE S C O R P O R A TE P R OF I L E 47
Sarcomere Directed Drug Development SKELETAL MUSCLE Reldesemtiv CK-601 48Sarcomere Directed Drug Development SKELETAL MUSCLE Reldesemtiv CK-601 48
Sarcomere Directed Drug Development Skeletal muscle The sarcomere is a molecular structure found in skeletal and cardiac muscle that enables skeletal myocytes to contract and generate force Troponin Activate Activate Reldesemtiv CK-601 (Skeletal) (Skeletal) Tropomyosin Actin Calcium Thin filament ATP Myosin Myosin head lever arm Thick filament O V E R V I E W C A R D I A C C A N D I D A TE S S K E L E T A L C A N D I D A T E S C O R P OR A T E P R O F IL E 49 49Sarcomere Directed Drug Development Skeletal muscle The sarcomere is a molecular structure found in skeletal and cardiac muscle that enables skeletal myocytes to contract and generate force Troponin Activate Activate Reldesemtiv CK-601 (Skeletal) (Skeletal) Tropomyosin Actin Calcium Thin filament ATP Myosin Myosin head lever arm Thick filament O V E R V I E W C A R D I A C C A N D I D A TE S S K E L E T A L C A N D I D A T E S C O R P OR A T E P R O F IL E 49 49
Phase 2 Clinical Trial in ALS Results presented at American Academy of Neurology 2019 Double-Blind, Placebo-Controlled: 12 weeks Placebo (n = 110) Parallel group, dose ranging study enrolled 458 patients with ALS in the US, Canada, 150 mg BID (n = 110) Australia and Europe evaluating change from Screening Follow-up 2 weeks 4 weeks baseline in the percent predicted slow vital 300 mg BID (n = 110) capacity (SVC) at 12 weeks of treatment with reldesemtiv or placebo 450 mg BID (n = 110) Randomization 1:1:1:1 End of Dosing O V E R V I E W C A R D I A C C A N D I D A TE S S K E L E T A L C A N D I D A T E S C O R P OR A T E P R O F IL E 50Phase 2 Clinical Trial in ALS Results presented at American Academy of Neurology 2019 Double-Blind, Placebo-Controlled: 12 weeks Placebo (n = 110) Parallel group, dose ranging study enrolled 458 patients with ALS in the US, Canada, 150 mg BID (n = 110) Australia and Europe evaluating change from Screening Follow-up 2 weeks 4 weeks baseline in the percent predicted slow vital 300 mg BID (n = 110) capacity (SVC) at 12 weeks of treatment with reldesemtiv or placebo 450 mg BID (n = 110) Randomization 1:1:1:1 End of Dosing O V E R V I E W C A R D I A C C A N D I D A TE S S K E L E T A L C A N D I D A T E S C O R P OR A T E P R O F IL E 50
Primary Endpoint: SVC Change from baseline in percent predicted SVC at week 12 -6.46 -4.97 -4.62 -4.58 0 -1 -2 -3 Primary Analysis* P = 0.11 -4 for weighted -5 dose-response relationship -6 -7 * -8 -9 Placebo 150 mg BID 300 mg BID 450 mg BID *Based on Mixed Model for Repeated Measures (MMRM) with the contrasts of (-5, -1, 3, 3) for placebo, reldesemtiv 150 mg, 300 mg and 450 mg BID, respectively O V E R V I E W C A R D I A C C A N D I D A TE S S K E L E T A L C A N D I D A T E S C O R P OR A T E P R O F IL E 51 Percent Predicted SVC Change From Baseline at Week 12 (95% CI)Primary Endpoint: SVC Change from baseline in percent predicted SVC at week 12 -6.46 -4.97 -4.62 -4.58 0 -1 -2 -3 Primary Analysis* P = 0.11 -4 for weighted -5 dose-response relationship -6 -7 * -8 -9 Placebo 150 mg BID 300 mg BID 450 mg BID *Based on Mixed Model for Repeated Measures (MMRM) with the contrasts of (-5, -1, 3, 3) for placebo, reldesemtiv 150 mg, 300 mg and 450 mg BID, respectively O V E R V I E W C A R D I A C C A N D I D A TE S S K E L E T A L C A N D I D A T E S C O R P OR A T E P R O F IL E 51 Percent Predicted SVC Change From Baseline at Week 12 (95% CI)
Change From Baseline: All Active vs Placebo* Results support progression to potential Phase 3 clinical trial SVC Change From Baseline ALSFRS-R Change From Baseline (All Active vs Placebo) (All Active vs Placebo) 0.0 0.0 *P = 0.10 *P = 0.01 LS Mean (SE) Difference LS Mean (SE) in Change of % Difference in Change -1.0 Predicted SVC 1.7 (1.1) of ALSFRS-R 0.9 (0.3) -2.5 -2.0 -5.0 -3.0 Relative reduction of 27% Relative reduction of 25% in decline of percent predicted in drop of ALSFRS-R -7.5 -4.0 SVC compared with placebo compared to placebo -5.0 -10.0 12 Weeks of Dosing Off Drug 12 Weeks of Dosing Off Drug Week 16/ Week 16/ Week 8 Baseline Week 2 Week 4 Week 8 Week 12 Baseline Week 2 Week 4 Week 12 Follow-up Follow-up Visit Visit Study Treatment: Placebo All Active Study Treatment: Placebo All Active *post hoc analysis FORTITUDE-ALS did not achieve statistical significance, but patients on all dose groups of reldesemtiv declined less than patients on placebo O V E R V I E W C A R D I A C C A N D I D A TE S S K E L E T A L C A N D I D A T E S C O R P OR A T E P R O F IL E 52 LS Mean (±SE) of Change in Percent Predicted SVC From Baseline LS Mean (±SE) of Change in Functional Rating Scale – Revised (ALSFRS-R) From BaselineChange From Baseline: All Active vs Placebo* Results support progression to potential Phase 3 clinical trial SVC Change From Baseline ALSFRS-R Change From Baseline (All Active vs Placebo) (All Active vs Placebo) 0.0 0.0 *P = 0.10 *P = 0.01 LS Mean (SE) Difference LS Mean (SE) in Change of % Difference in Change -1.0 Predicted SVC 1.7 (1.1) of ALSFRS-R 0.9 (0.3) -2.5 -2.0 -5.0 -3.0 Relative reduction of 27% Relative reduction of 25% in decline of percent predicted in drop of ALSFRS-R -7.5 -4.0 SVC compared with placebo compared to placebo -5.0 -10.0 12 Weeks of Dosing Off Drug 12 Weeks of Dosing Off Drug Week 16/ Week 16/ Week 8 Baseline Week 2 Week 4 Week 8 Week 12 Baseline Week 2 Week 4 Week 12 Follow-up Follow-up Visit Visit Study Treatment: Placebo All Active Study Treatment: Placebo All Active *post hoc analysis FORTITUDE-ALS did not achieve statistical significance, but patients on all dose groups of reldesemtiv declined less than patients on placebo O V E R V I E W C A R D I A C C A N D I D A TE S S K E L E T A L C A N D I D A T E S C O R P OR A T E P R O F IL E 52 LS Mean (±SE) of Change in Percent Predicted SVC From Baseline LS Mean (±SE) of Change in Functional Rating Scale – Revised (ALSFRS-R) From Baseline
Subgroup Analyses* ALSFRS-R Total Score Percent Predicted SVC No. of Patients LSM Difference No. of Patients LSM Difference (pbo/reldesemtiv) (95% Cl) Estimate P value (pbo/reldesemtiv) (95% Cl) Estimate P value Percent predicted SVC at baseline Percent predicted SVC at baseline <80 38/102 1.037 0.5935 <80 43/109 1.588 0.0089 ≥80 52/187 2.135 0.0834 ≥80 57/196 0.264 0.5296 ALSFRS-R total score at baseline ALSFRS-R total score at baseline <Median (38.0) 43/118 2.886 0.1.41 <Median (38.0) 48/129 1.107 0.0585 ≥Median (38.0) 47/171 0.451 0.7146 ≥Median (38.0) 52/176 0.685 0.0987 ALSAQ-5 total score at baseline ALSAQ-5 total score at baseline <150 49/159 0.568 0.6689 <150 52/164 0.266 0.5025 ≥150 41/130 3.489 0.0287 ≥150 48/141 1.598 0.0055 Anatomic site of disease onset Anatomic site of disease onset Limb 73/234 2.309 0.0448 Limb 80/245 0.872 0.0279 Bulbar 17/55 -0.027 0.9923 Bulbar 20/60 0.861 0.2194 Time since ALS symptom onset Time since ALS symptom onset <2 Years 50/188 0.530 0.7211 <2 Years 56/199 1.422 0.0025 ≥2 Years 40/101 3.640 0.0094 ≥2 Years 44/106 0.475 0.3439 Time since ALS diagnosis Time since ALS diagnosis <1 Year 65/210 0.819 0.5263 <1 Year 71/225 1.123 0.0101 ≥1 Year 25/79 4.237 0.0172 ≥1 Year 29/80 0.359 0.5350 <6 Months 39/130 1.230 0.4538 <6 Months 42/137 1.359 0.0154 ≥6 Months 51/159 2.285 0.1024 ≥6 Months 58/168 0.566 0.1820 Pre-study rate of disease progression Pre-study rate of disease progression (ALSFRS-R total score reduction per month) (ALSFRS-R total score reduction per month) st st 1 tertile ≤(0.3667) 29/107 0.663 0.6361 1 tertile ≤(0.3667) 32/110 0.389 0.4298 nd nd 2 tertile > (0.3667) – (0.6673) 35/94 2.960 0.0976 2 tertile > (0.3667) – (0.6673) 38/99 0.987 0.0665 rd rd 3 tertile (0.6673) 26/88 1.620 0.4597 3 tertile (0.6673) 30/96 1.733 0.0177 -15 -10 -5 0 5 10 15 -5 -2.5 0 2.5 5 Favors Placebo Favors Treatment Favors Placebo Favors Treatment *FORTITUDE-ALS did not achieve statistical significance, but patients on all dose groups of reldesemtiv declined less than patients on placebo O V E R V I E W C A R D I A C C A N D I D A TE S S K E L E T A L C A N D I D A T E S C O R P OR A T E P R O F IL E 53Subgroup Analyses* ALSFRS-R Total Score Percent Predicted SVC No. of Patients LSM Difference No. of Patients LSM Difference (pbo/reldesemtiv) (95% Cl) Estimate P value (pbo/reldesemtiv) (95% Cl) Estimate P value Percent predicted SVC at baseline Percent predicted SVC at baseline <80 38/102 1.037 0.5935 <80 43/109 1.588 0.0089 ≥80 52/187 2.135 0.0834 ≥80 57/196 0.264 0.5296 ALSFRS-R total score at baseline ALSFRS-R total score at baseline <Median (38.0) 43/118 2.886 0.1.41 <Median (38.0) 48/129 1.107 0.0585 ≥Median (38.0) 47/171 0.451 0.7146 ≥Median (38.0) 52/176 0.685 0.0987 ALSAQ-5 total score at baseline ALSAQ-5 total score at baseline <150 49/159 0.568 0.6689 <150 52/164 0.266 0.5025 ≥150 41/130 3.489 0.0287 ≥150 48/141 1.598 0.0055 Anatomic site of disease onset Anatomic site of disease onset Limb 73/234 2.309 0.0448 Limb 80/245 0.872 0.0279 Bulbar 17/55 -0.027 0.9923 Bulbar 20/60 0.861 0.2194 Time since ALS symptom onset Time since ALS symptom onset <2 Years 50/188 0.530 0.7211 <2 Years 56/199 1.422 0.0025 ≥2 Years 40/101 3.640 0.0094 ≥2 Years 44/106 0.475 0.3439 Time since ALS diagnosis Time since ALS diagnosis <1 Year 65/210 0.819 0.5263 <1 Year 71/225 1.123 0.0101 ≥1 Year 25/79 4.237 0.0172 ≥1 Year 29/80 0.359 0.5350 <6 Months 39/130 1.230 0.4538 <6 Months 42/137 1.359 0.0154 ≥6 Months 51/159 2.285 0.1024 ≥6 Months 58/168 0.566 0.1820 Pre-study rate of disease progression Pre-study rate of disease progression (ALSFRS-R total score reduction per month) (ALSFRS-R total score reduction per month) st st 1 tertile ≤(0.3667) 29/107 0.663 0.6361 1 tertile ≤(0.3667) 32/110 0.389 0.4298 nd nd 2 tertile > (0.3667) – (0.6673) 35/94 2.960 0.0976 2 tertile > (0.3667) – (0.6673) 38/99 0.987 0.0665 rd rd 3 tertile (0.6673) 26/88 1.620 0.4597 3 tertile (0.6673) 30/96 1.733 0.0177 -15 -10 -5 0 5 10 15 -5 -2.5 0 2.5 5 Favors Placebo Favors Treatment Favors Placebo Favors Treatment *FORTITUDE-ALS did not achieve statistical significance, but patients on all dose groups of reldesemtiv declined less than patients on placebo O V E R V I E W C A R D I A C C A N D I D A TE S S K E L E T A L C A N D I D A T E S C O R P OR A T E P R O F IL E 53
Post-Hoc Analyses Inform Potential Path Forward Change From Baseline in ALSFRS-R Probability of No New DME* Over Time by Progressor Tertiles With Treatment With Reldesemtiv DME (Durable Medical Equipment): Manual wheelchair, power wheelchair, NIV, Augmentative Language Device, PEG Time (weeks) 0 1.0 0 2 4 6 8 10 12 14 -0.5 0.9 -1 -1.5 0.8 Patients on -2 reldesemtiv had significantly lower risk -2.5 (38%) of agreeing to receive DME 0.7 compared to placebo Treatment difference -3 1.15; P = 0.0112 -3.5 0.6 -4 342 328 300 264 114 104 93 80 -4.5 0 4 8 12 Weeks on Treatment SP reldesemtiv combined (n=117) SP placebo (n=35) MP + FP reldesemtiv combined (n=227) MP + FP placebo (n=79) All Active Placebo O V E R V I E W C A R D I A C C A N D I D A TE S S K E L E T A L C A N D I D A T E S C O R P OR A T E P R O F IL E 54 LS mean change from baseline in ALSFRS-R Probability of No New DMEPost-Hoc Analyses Inform Potential Path Forward Change From Baseline in ALSFRS-R Probability of No New DME* Over Time by Progressor Tertiles With Treatment With Reldesemtiv DME (Durable Medical Equipment): Manual wheelchair, power wheelchair, NIV, Augmentative Language Device, PEG Time (weeks) 0 1.0 0 2 4 6 8 10 12 14 -0.5 0.9 -1 -1.5 0.8 Patients on -2 reldesemtiv had significantly lower risk -2.5 (38%) of agreeing to receive DME 0.7 compared to placebo Treatment difference -3 1.15; P = 0.0112 -3.5 0.6 -4 342 328 300 264 114 104 93 80 -4.5 0 4 8 12 Weeks on Treatment SP reldesemtiv combined (n=117) SP placebo (n=35) MP + FP reldesemtiv combined (n=227) MP + FP placebo (n=79) All Active Placebo O V E R V I E W C A R D I A C C A N D I D A TE S S K E L E T A L C A N D I D A T E S C O R P OR A T E P R O F IL E 54 LS mean change from baseline in ALSFRS-R Probability of No New DME
Convergence of Verticals Addresses CV Conditions & Co-Morbidities • HFrEF þ Enhanced Cardiac • HCM þ Muscle Performance • HFpEF Applicable Across • Other Cardiomyopathies Additional • Right Ventricle (RV) CV Conditions Dysfunction Enhanced Skeletal • Frailty Muscle Performance • Reduced Work Capacity Can Address CV CV Patient • Muscle Weakness Patient Co-Morbidities O V E R V I E W C A R D I A C C A N D I D A TE S S K E L E T A L C A N D I D A T E S C O R P OR A T E P R O F IL E 55Convergence of Verticals Addresses CV Conditions & Co-Morbidities • HFrEF þ Enhanced Cardiac • HCM þ Muscle Performance • HFpEF Applicable Across • Other Cardiomyopathies Additional • Right Ventricle (RV) CV Conditions Dysfunction Enhanced Skeletal • Frailty Muscle Performance • Reduced Work Capacity Can Address CV CV Patient • Muscle Weakness Patient Co-Morbidities O V E R V I E W C A R D I A C C A N D I D A TE S S K E L E T A L C A N D I D A T E S C O R P OR A T E P R O F IL E 55
Sarcomere Directed Therapies CORPORATE PROFILE 56Sarcomere Directed Therapies CORPORATE PROFILE 56
We’re Up To The Challenge Pivotal trial Development Pivotal trials Potential FDA Clinical stage readout in programs by Pipeline* in 2021 approvals by 2025 programs 1 2 3 5 10 Q4 2020 2025 Heart Failure HCM ALS Ongoing Omecamtiv mecarbil CK-274 Reldesemtiv R&D o Phase 3 CV outcomes Programs* o Phase 2 trial o Phase 3 trial trial results Q4 2020 Additional research initial results starting in AMG-594 o Phase 3 exercise capacity in muscle biology, 2H 2020 Q4 2020 o Phase 1 trial results 2H 2021 energetics & metabolism ~20% >$1B 175 Foundations $237M Eligible for double-digit Eligible milestone Full time escalating royalties** on At Q1 2020 payments in partnerships employees worldwide sales on omecamtiv mecarbil *Timelines and milestones reflect Cytokinetics' **Outside Japan; lower royalty rate in Japan current expectations and beliefs. O V E R V I E W C A R D I A C C A N D I D A TE S S K E L E T A L C A N D I D A TE S C O R P O R A T E P R O F I L E 57We’re Up To The Challenge Pivotal trial Development Pivotal trials Potential FDA Clinical stage readout in programs by Pipeline* in 2021 approvals by 2025 programs 1 2 3 5 10 Q4 2020 2025 Heart Failure HCM ALS Ongoing Omecamtiv mecarbil CK-274 Reldesemtiv R&D o Phase 3 CV outcomes Programs* o Phase 2 trial o Phase 3 trial trial results Q4 2020 Additional research initial results starting in AMG-594 o Phase 3 exercise capacity in muscle biology, 2H 2020 Q4 2020 o Phase 1 trial results 2H 2021 energetics & metabolism ~20% >$1B 175 Foundations $237M Eligible for double-digit Eligible milestone Full time escalating royalties** on At Q1 2020 payments in partnerships employees worldwide sales on omecamtiv mecarbil *Timelines and milestones reflect Cytokinetics' **Outside Japan; lower royalty rate in Japan current expectations and beliefs. O V E R V I E W C A R D I A C C A N D I D A TE S S K E L E T A L C A N D I D A TE S C O R P O R A T E P R O F I L E 57
Upcoming 2020 Milestones Expect Topline Results from Expect Data from Cohort 1 of Expect to Complete Enrollment GALACTIC-HF in Q4 REDWOOD-HCM in 2H in METEORIC-HF Conduct Commercial Readiness Prepare for Potential Phase 3 & Develop Co-Promotion Plan Clinical Trial of Reldesemtiv in for Omecamtiv Mecarbil Patients with ALS O V E R V I E W C A R D I A C C A N D I D A TE S S K E L E T A L C A N D I D A TE S C O R P O R A T E P R O F I L E 58Upcoming 2020 Milestones Expect Topline Results from Expect Data from Cohort 1 of Expect to Complete Enrollment GALACTIC-HF in Q4 REDWOOD-HCM in 2H in METEORIC-HF Conduct Commercial Readiness Prepare for Potential Phase 3 & Develop Co-Promotion Plan Clinical Trial of Reldesemtiv in for Omecamtiv Mecarbil Patients with ALS O V E R V I E W C A R D I A C C A N D I D A TE S S K E L E T A L C A N D I D A TE S C O R P O R A T E P R O F I L E 58
Sarcomere Directed Therapies THANK YOU John, diagnosed with heart failure Jillian, diagnosed with HCM Chuck, diagnosed with ALSSarcomere Directed Therapies THANK YOU John, diagnosed with heart failure Jillian, diagnosed with HCM Chuck, diagnosed with ALS