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| Item 8.01 | Other Events |
On May 22, 2024, Cytokinetics, Incorporated released its current corporate presentation, which is attached hereto as Exhibit 99.1 and is incorporated by reference in this Item 8.01.
| Item 9.01 | Financial Statements and Exhibits. |
(d) Exhibits
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Description | |
| 99.1 | Corporate Presentation. | |
| 104 | Cover Page Interactive Data File (embedded within the Inline XBRL document) | |
SIGNATURE
Pursuant to the requirements of the Securities Exchange Act of 1934, as amended, the Registrant has duly caused this report to be signed on its behalf by the undersigned hereunto duly authorized.
| CYTOKINETICS, INCORPORATED | ||||||
| Date: May 22, 2024. | ||||||
| By: | /s/ Robert Blum | |||||
| Robert Blum | ||||||
| Chief Executive Officer | ||||||
Exhibit 99.1 EMPOWERING muscle EMPOWERING lives
Forward-Looking Statements This presentation contains forward-looking statements for purposes of the Private Securities Litigation Reform Act of 1995 (the “Act”). Cytokinetics, Incorporated (“Cytokinetics” or the “Company”) 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 express or implied related to Cytokinetics’ 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, hypertrophic cardiomyopathy (HCM) or heart failure with preserved ejection fraction (HFpEF); projections regarding the size of the addressable patient population for aficamten, omecamtiv mecarbil, CK-136, CK-586 or any of our other drug candidates; Cytokinetics’ commercial readiness for aficamten or omecamtiv mecarbil; our ability to submit a new drug application for aficamten with FDA in the third quarter 2024 or a marketing authorization application with EMA in the fourth quarter 2024, the likelihood and/or timing of regulatory approval for our planned new drug application for aficamten, omecamtiv mecarbil or any future new drug application for any of our other drug candidates or the anticipated timing of any interactions with FDA, EMA or any other regulatory authorities in connection thereto; the timing of completion of MAPLE-HCM, ACACIA-HCM, CEDAR-HCM or any of our other clinical trials, the efficacy or safety of aficamten, omecamtiv mecarbil, CK-136, CK-586 or any of our other drug candidates, our ability to fully enroll or to announce the results of any of our clinical trials by any particular date; the properties, potential benefits and commercial potential of aficamten, omecamtiv mecarbil, CK-136, CK-586 or any of 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’ ability to conduct clinical trials, and Cytokinetics may be unable to obtain or maintain patent or trade secret protection for its intellectual property; 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; and competitive products or alternative therapies may be developed by others for the treatment of indications Cytokinetics’ drug candidates and potential drug candidates may target. 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 (the “SEC”). Disclaimer This presentation concerns drug candidates that are under clinical investigation, and which have not yet been approved by the U.S. Food and Drug Administration. These are currently limited by federal law to investigational use, and no representation is made as to their safety or effectiveness for the purposes for which they are being investigated. The assumptions used in the preparation of this presentation, although considered reasonable by us at the time of preparation, may prove to be incorrect. You are cautioned that the information is based on assumptions as to many factors and that actual results may vary from the results projected and such variations may be material. Accordingly, you should not place undue reliance on any forward-looking statements contained herein or rely on them as predictions of future events. The trademarks, trade names and service marks appearing in this presentation are the property of their respective owners. Certain information contained in this presentation relate to or are based on studies, publications and other data obtained from third-party sources as well as our own internal estimates and research. While we believe these third-party sources to be reliable as of the date of this presentation, we have not independently verified, and make no representation as to the adequacy, fairness, accuracy or completeness of, any information obtained from third-party sources. 2
Structured Financing Transaction with Royalty Pharma Four Separate Components Providing $250M upon Closing; up to $575M Total Royalty Pharma R&D Partnership, Royalty Monetization, Long-term Debt and Equity Investment Diversifies access to capital to support potential commercial launch and monetize/advance myosin focused pipeline CK-586: R&D Funding Aficamten: Potential Commercial Launch Omecamtiv Mecarbil: R&D Funding Capital Cytokinetics to receive $50M upfront in exchange Cytokinetics to receive $100M in upfront capital for 1.0% royalty on net sales of CK-586 to fund confirmatory Phase 3 clinical trial Cytokinetics to receive $50M upfront capital Royalty Pharma will have option to invest up to If new Phase 3 clinical trial is positive and FDA Cytokinetics eligible to draw additional $175M additional $150M for Phase 3 development approval is received within specified time frames, within 12 months of FDA approval for oHCM Royalty Pharma will receive 1.0x milestone If Royalty Pharma opts in to Phase 3 funding, it will Capital repayable over 10 years in quarterly payment and incremental 2.0% royalty on global be eligible to receive up to 0.75x milestone upon installments (totaling 1.9x) net sales and/or fixed quarterly payments certain regulatory approvals and 4.5% royalty on global net sales Otherwise Cytokinetics required to repay loan in fixed quarterly payments (totaling 2.275x – If Royalty Pharma does not opt in to Phase 3 2.375x) over either 18 or 22 quarters funding, eligible for 1% royalty on global net sales Royalty Pharma’s royalty on aficamten was restructured so that Royalty Pharma will now receive 4.5% up to $5.0 billion of annual net sales of aficamten and 1% above $5.0 billion of annual net sales compared to the prior 4.5% up to $1.0 billion of annual net sales and 3.5% above $1.0 billion of annual net sales Royalty Pharma to purchase $50M of Cytokinetics’ common stock, at Cytokinetics’ option, subject to certain conditions 3
Achieve regulatory approvals for drugs arising from our pipeline Build commercial capabilities to market and sell our medicines reflective of their innovation and value 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 pioneering medicines Leading with Science, Expand our development 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 4
Sarcomere Directed Drug Development The sarcomere is a molecular structure found in skeletal and cardiac muscle that enables myocytes to contract and generate force ACTIVATE INHIBIT INHIBIT ACTIVATE Troponin Omecamtiv CK-136 Aficamten CK-586 Mecarbil (Cardiac) (Cardiac) (Cardiac) Myosin (Cardiac) Tropomyosin Actin Calcium Thin filament Myosin ATP head Myosin lever arm Thick filament 5 5
A Commitment to Muscle-Directed Cardiac Medicines Building a specialty cardiology franchise anchored by aficamten Protein Target Therapeutic Area Drug Candidate Research Pre-Clinical Phase 1 Phase 2 Phase 3 Approval Preparing for regulatory oHCM Aficamten submissions in 2H 2024 Myosin oHCM Aficamten (First-line*) Pediatric oHCM Aficamten Myosin-Targeted Therapy nHCM Aficamten HFpEF CK-586 Omecamtiv HFrEF Mecarbil Troponin Troponin- Heart Failure, CK-136 Targeted Therapy other Muscle Biology Other Biology Research Directed *Pending results from MAPLE-HCM, an ongoing Phase 3 clinical trial evaluating for the potential superiority of aficamten as monotherapy compared to metoprolol as monotherapy in patients with obstructive HCM. All drug candidates above are investigational products and are not approved as safe or effective for any indication. 6
Building a Specialty Cardiology Franchise Anchored by Aficamten Potential patient market for specialty cardiology franchise strategy Myosin-Targeted Therapies Myosin Troponin CK-136 Troponin-Targeted Therapies Heart failure 3 800K Potential to HFpEF + EF ≥ 65% expand to in 2030 subsets of heart Omecamtiv failure Mecarbil HFrEF 1,2 250-400K Potential in nHCM patients HFrEF in Europe in 2027 CK-586 1,2 450-700K HFpEF oHCM patients With nHCM as a in 2025-2026 proxy, potential to expand into Aficamten HFpEF nHCM All drug candidates above are investigational products and are not ACACIA-HCM approved as safe or effective for any indication. Aficamten Potential to 1. Cardiovascular Research Group: CVrg Market Strategies: Heart Failure, p 48, Q4 2022; Maron BJ: et al: Prevalence of Hypertrophic Cardiomyopathy In Aficamten expand into A General Population of Young Adults, Circulation 1995;92;785-789; oHCM Estimated nHCM Semsarian C. et al: New Perspectives on the Prevalence of Hypertrophic oHCM MAPLE-HCM Cardiomyopathy, J. Am, Coll. Cardiol. 2015; 65: 1249-1254; prevalence in 2. Lu DY et al: Clinical Outcomes in Patients With Nonobstructive, Labile, and SEQUOIA-HCM Potential to US only Obstructive Hypertrophic Cardiomyopathy. J. Am. Heart Assoc. 2018;7:1-11 First potential expand to 3. Dunlay et al (2012) Circ Heart Fail. 2012 Nov;5(6):720-6. doi: 10.1161/CIRCHEARTFAILURE.111.966366. Epub 2012 Aug 30. indication first-line treatment 7
Aficamten 8
Opportunity for CMIs in Diagnosed, Symptomatic HCM Patients 1 Prevalence of HCM 700K to 1.1M ~65% ~35% 1,3 1,3 Diagnosed HCM oHCM nHCM US US 2 ~300K oHCM Prevalence nHCM Prevalence 1,3 1,3 450-700K 250-400K Diagnosed oHCM Diagnosed nHCM 2,3 2,3 ~200K ~100K Sympt. Sympt. 4,5 4,5 >130K >40K Projections and forecasts for illustration. 1. Cardiovascular Research Group: CVrg Market Strategies: Heart Failure, p 48, Q4 2022; Maron BJ: et al:: Prevalence of Hypertrophic Cardiomyopathy In A General Population of Young Adults, Circulation 1995;92;785-789; Semsarian C. et al: New Perspectives on the Prevalence of Hypertrophic Cardiomyopathy, J. Am, Coll. Cardiol. 2015; 65: 1249-1254; 2. DoF: SHA; Symphony PTD (Patient Transaction Data): Includes patients diagnosed since 2016 and having any HC transaction in the claims data universe in the last year June 2022-May 2023); 3. Lu DY et al: Clinical Outcomes in Patients With Nonobstructive, Labile, and Obstructive Hypertrophic Cardiomyopathy. J. Am. Heart Assoc.2018;7:1-11 4. DoF: SHA Symphony PTD (Patient Transaction Data) includes any patients with symptoms in the last 2 years: angina, dyspnea, fatigue, palpitations, syncope, tachycardia; and/or treatments in the past 2 years: bb, ccb, dyso, ralo, Camzyos; 5. DoF Primary market research: 443 HCPs treating HCM - % of nHCM patients not considered under control with current SOC. 9
Aficamten: Mechanism of Action Aficamten stabilized myosin in the released post-powerstroke state unable to hydrolyze ATP “Fewer hands pulling on the rope” Before Aficamten After Aficamten Mechanochemical domain ATP AF Post-Powerstroke State Actin sliding Actin sliding Aficamten is an investigational drug and is not approved by any regulatory agency. Its safety and efficacy have not been established. 10
Aficamten: Aspirational Target Profile Potential next-in-class cardiac myosin inhibitor No clinically Rapid Rapid Speed to Predictable No meaningful onset reversibility optimal dose dose response teratogenicity P450 liabilities Aspirational information. Aficamten is an investigational drug and is not approved by any regulatory agency. Its safety and efficacy have not been established. 11
Aficamten: Clinical Development Plan for HCM Phase 2 Phase 1 Phase 3 SAD & MAD REDWOOD-HCM Cohorts 1-3 SEQUOIA-HCM Healthy obstructive HCM obstructive HCM Target Volunteers Placebo controlled; echocardiography endpoints Pivotal trial with exercise endpoint (peak VO2) IND Filed NDA Potential for Well tolerated dose Improved LVOT gradient approval based with desired PD effects on results from MAPLE-HCM SEQUOIA-HCM obstructive HCM Phase 1 Aficamten monotherapy vs. Metoprolol monotherapy Study in healthy Japanese REDWOOD-HCM Cohort 4 ACACIA-HCM volunteers non-obstructive HCM non-obstructive HCM Proof of activity Pivotal trial in patients with symptomatic nHCM KEY Complete CEDAR-HCM Pediatric obstructive HCM Ongoing Trial in a pediatric population with symptomatic oHCM Not Yet Started FOREST-HCM obstructive & non-obstructive HCM Extension study for long-term safety & efficacy Aficamten is an investigational drug and is not approved by any regulatory agency. Its safety and efficacy have not been established. 12
SEQUOIA-HCM: Phase 3 Trial Primary endpoint: Change in pVO by 2 CPET from baseline to Week 24 Patients with Aficamten + SoC oHCM treated 1 with SOC with Secondary objectives include measuring post-Valsalva peak LVOT-G change in KCCQ & improvement in 1 ≥50 mmHg & NYHA class II/III Placebo + SoC NYHA class at week 12 and 24 Enrolled 282 patients treated with Study Visits standard of care with: Screen D1 W2 W4 W6 W8 W12 W16 W20 W24 W28 - resting LVOT-G ≥30 mmHg, * * * * Echocardiogram - post-Valsalva LVOT-G ≥50 mmHg, CPET - NYHA Class II or III, KCCQ - exercise performance <80% predicted NYHA Echocardiogram Individualized dose up-titration based on Dose Options (Dose optimization completed by Week 8) echocardiography: LVEF ≥55%, post-Valsalva LVOT-G ≥30 mmHg 5 mg QD 10 mg QD 15 mg QD 20 mg QD SOC: standard of care * Focused echocardiogram 13 Screening Randomization End of Study
SEQUOIA-HCM: Baseline Characteristics Baseline characteristics reflect highly symptomatic patient population with reduced exercise capacity Aficamten Placebo Aficamten Placebo n=142 n=140 n=142 n=140 Background HCM therapy, n (%) Age, y 59.2 ± 12.6 59.0 ± 13.4 Beta-blocker 86 (60.6) 87 (62.1) Female sex, n (%) 56 (39.4) 59 (42.1) • Significant symptom Calcium channel blocker 45 (31.7) 36 (25.7) Race, n (%) burden despite Disopyramide 16 (11.3) 20 (14.3) background therapy White 108 (76.1) 115 (82.1) None 19 (13.4) 22 (15.7) Geographic region, n (%) KCCQ-CSS 76 ± 18 74 ± 18 • 61% of patients on North America 49 (34.5) 45 (32.1) NYHA FC, n (%) beta-blockers China 24 (16.9) 22 (15.7) II 108 (76.1) 106 (75.7) Europe and Israel 69 (48.6) 73 (52.1) III/IV 34 (23.9) 34 (24.3) • Baseline pVO 2 Medical history, n (%) Median NT-proBNP (IQR), pg/mL 818 (377–1630) 692 (335–1795) reflects patient Hypertension 75 (52.8) 70 (50.0) population with Median hs-cTnl (IQR), ng/L 12.9 (7.6–33.6) 11.5 (7.7–25.0) Paroxysmal atrial fibrillation 21 (14.8) 20 (14.3) reduced exercise Echocardiographic parameters Permanent atrial fibrillation 2 (1.4) 1 (0.7) capacity Valsalva LVOT-G, mmHg 82.9 ± 32 83.3 ± 33 CPET Resting LVOT-G, mmHg 54.8 ± 27 55.3 ± 32 pVO (mL/kg/min) 18.5 (4.5) 18.6 (4.5) 2 LVEF, % 74.8 ± 5.5 74.8 ± 6.3 Percent of predicted pVO (%) 58 (13) 57 (12) Maximal LV wall thickness, mm 20.7 ± 3.0 21.0 ± 3.0 2 Values are the mean ± SD unless otherwise indicated. Aficamten is an investigational drug and is not approved by any regulatory agency. Its safety and efficacy have not been established. Maron M. “Aficamten for the Treatment of Symptomatic Obstructive Hypertrophic Cardiomyopathy”. ESC Heart Failure 2024. 14
SEQUOIA-HCM: Dosing Mean ± SD, n (%), or median Placebo 5 mg 10 mg 15 mg 20 mg (IQR) n=140 n=5 n=18 n=49 n=68 Aficamten dose at Week 8 % per treatment group 100% 3.5% 12.7% 34.5% 47.9% (end of titration) Background HCM therapy Beta-blocker 87 (62.1) 5 (100.0) 10 (55.6) 31 (63.3) 40 (58.8) 3% Calcium channel blocker 36 (25.7) 1 (20.0) 3 (16.7) 17 (34.7) 24 (35.3) 13% Disopyramide 20 (14.3) 1 (20.0) 5 (27.8) 3 (6.1) 7 (10.3) Baseline study assessments KCCQ-CSS 74 ± 18 68 ± 26 75 ± 19 77 ± 20 75 ± 17 NYHA class II 106 (75.7) 3 (60.0) 16 (88.9) 33 (67.3) 54 (79.4) 49% 5 mg 692 1133 338 871 962 NT-proBNP, pg/mL (335, 1795) (992, 1475) (283, 674) (428, 1505) (511, 2085) 10 mg hs-cTnI, ng/L 12 (8, 25) 12 (6, 234) 10 (5, 17) 13 (7, 24) 16 (8, 38) 35% 15 mg pVO , mL/kg/min 18.6 ± 4.5 18.7 ± 2.9 18.6 ± 3.9 18.2 ± 4.1 18.3 ± 4.9 2 20 mg Echocardiographic parameters (core laboratory) LVEF at baseline, % 75 ± 6 71 ± 12 76 ± 5 75 ± 5 75 ± 5 Peak LVOT-G at rest 55 ± 32 29 ± 13 45 ± 21 56 ± 24 58 ± 30 There were no differences in age, sex, ethnicity, body mass index, or Peak LVOT-G post-Valsalva 83 ± 33 51 ± 24 71 ± 29 84 ± 26 88 ± 35 comorbidities (diabetes, hypertension or AF) between dose groups Left ventricular MWT, cm 2.10 ± 0.30 2.42 ± 0.74 1.94 ± 0.22 2.04 ± 0.26 2.11 ± 0.28 Aficamten is an investigational drug and is not approved by any regulatory agency. Its safety and efficacy have not been established. hs-cTnl, high-sensitive cardiac troponin; IQR, interquartile range; KCCQ-CSS, Kansas City Cardiomyopathy Questionnaire-Clinical Summary score; MWT, maximal wall thickness; NT-proBNP, N-terminal pro b-type natriuretic peptide; NYHA, New York Heart Association. Coats CJ. “Dosing and Safety Profile of Aficamten in Symptomatic Obstructive Hypertrophic Cardiomyopathy”. ESC Heart Failure 2024. 15
SEQUOIA-HCM: Primary Endpoint Significant improvement in exercise capacity compared to placebo Results presented at Heart Failure 2024 and published in NEJM Absolute Change from Baseline to Week 24 LS mean Change from Baseline to Week 24 P=0.000002 Aficamten 2.5 Placebo 21 2.0 1.5 Data are mean and 95% CI 20 1.0 LS mean difference (SE) vs placebo: 1.74 mL/kg/min (0.36) 19 0.5 ΔpVO = 0.0 ml/kg/min 2 ΔpVO = 0.0 ml/kg/min 2 0.0 18 −0.5 Placebo Aficamten Baseline Week 24 Aficamten is an investigational drug and is not approved by any regulatory agency. Its safety and efficacy have not been established. Maron M. “Aficamten for the Treatment of Symptomatic Obstructive Hypertrophic Cardiomyopathy”. ESC Heart Failure 2024. 16 pVO (mL/kg/min) 2 ΔpVO (mL/kg/min) 2
SEQUOIA-HCM: Subgroup Analysis Results consistent across all prespecified subgroups including patients receiving or not receiving background beta-blockers Mean difference Mean difference n Aficamten Placebo n Aficamten Placebo (95% CI) (95% CI) (Afi/Plb) LS mean LS mean LS mean LS mean (Afi/Plb) Age Baseline NT-proBNP (median) <65 y 85/84 2.4 0.4 2.0 (1.1, 2.8) ≤ 788 pg/mL 66/73 2.2 0.6 1.7 (0.7, 2.7) ≥65 y 57/56 0.9 −0.5 1.4 (0.3, 2.5) > 788 pg/mL 73/65 1.4 −0.6 2.0 (1.0, 2.9) Sex CPET Modality Male 86/81 2.5 0.7 1.8 (0.9, 2.7) Treadmill 78/77 2.5 0.2 2.3 (1.4, 3.2) Female 56/59 Bicycle 0.6 −0.8 1.4 (0.4, 2.5) 64/63 0.9 −0.1 1.0 (−0.0, 2.1) Baseline BMI Baseline Median pVO 2 2 <30 kg/m 97/94 1.9 0.1 1.8 (1.0, 2.7) ≤18.4 mL/kg/min 1.5 −0.1 1.6 (0.6, 2.5) 74/67 2 ≥30 kg/m 45/46 1.4 −0.2 1.6 (0.3, 2.8) >18.4 mL/kg/min 68/73 2.0 0.1 1.9 (1.0, 2.9) Baseline Median LVEF Baseline Beta-Blocker Use ≤75.6% 73/68 1.9 0.0 1.8 (0.8, 2.8) Yes 1.4 −0.2 1.6 (0.7, 2.5) 86/87 >75.6% 69/72 No 1.7 0.0 1.6 (0.6, 2.6) 56/53 2.2 0.2 1.9 (0.8, 3.1) Baseline NYHA FC Baseline Resting LVOT (median) Class II 108/106 2.0 0.3 1.7 (0.9, 2.5) ≤51.1 mmHg 72/69 1.8 0.5 1.3 (0.3, 2.3) Class III /IV >51.1 mmHg 34/34 1.0 −0.9 1.9 (0.5, 3.3) 70/71 1.7 −0.4 2.1 (1.2, 3.1) Baseline Median KCCQ-CSS Genotype ≤78.1 67/75 1.7 −0.1 1.8 (0.8, 2.8) Positive 1.6 −1.0 2.6 (0.9, 4.2) 20/22 >78.1 75/65 1.8 0.1 1.7 (0.7, 2.6) Negative 71/70 1.4 −0.1 1.4 (0.5, 2.3) Interaction P values were >0.05 for all prespecified subgroups Favors Placebo Favors Treatment Favors Placebo Favors Treatment Aficamten is an investigational drug and is not approved by any regulatory agency. Its safety and efficacy have not been established. Maron M. “Aficamten for the Treatment of Symptomatic Obstructive Hypertrophic Cardiomyopathy”. ESC Heart Failure 2024. 17
SEQUOIA-HCM: Secondary Endpoints Statistically significant improvements in all 10 pre-specified secondary endpoints Endpoints P value Primary Endpoint pVO change from baseline to Week 24 <0.0001 2 Secondary Endpoints 1. KCCQ-CSS change from baseline to Week 24 <0.0001 2. NYHA Class Improvement by at least 1 class at Week 24 <0.0001 3. Valsalva LVOT-G change from baseline to Week 24 <0.0001 4. % Valsalva LVOT-G <30 mmHg at Week 24 <0.0001 5. Duration of SRT Eligible during 24 Weeks of Treatment <0.0001 6. KCCQ-CSS change from baseline to Week 12 <0.0001 7. NYHA Class Improvement by at least 1 class at Week 12 <0.0001 8. Valsalva LVOT-G change from baseline to Week 12 <0.0001 9. % Valsalva LVOT-G <30 mmHg at Week 12 <0.0001 10. Total workload change from baseline to Week 24 <0.0001 Aficamten is an investigational drug and is not approved by any regulatory agency. Its safety and efficacy have not been established. Maron M. “Aficamten for the Treatment of Symptomatic Obstructive Hypertrophic Cardiomyopathy”. ESC Heart Failure 2024. 18
SEQUOIA-HCM: Secondary & Exploratory Endpoints Significant improvement in post-Valsalva left ventricular outflow tract gradient (LVOT-G) LS mean difference: Resting LVOT-G Valsalva LVOT-G - 50 mmHg 100 100 90 90 80 80 70 70 60 60 50 50 40 40 30 30 20 20 0 2 4 6 8 12 16 20 24 28 0 2 4 6 8 12 16 20 24 28 Weeks Weeks Aficamten Placebo Washout Aficamten is an investigational drug and is not approved by any regulatory agency. Its safety and efficacy have not been established. Error bars are 95% CI Maron M. “Aficamten for the Treatment of Symptomatic Obstructive Hypertrophic Cardiomyopathy”. ESC Heart Failure 2024. 19 Resting LVOT-G (mmHg) Valsalva LVOT-G (mmHg)
SEQUOIA-HCM: Secondary & Exploratory Endpoints LS mean difference: ≥1 NYHA FC Improvement KCCQ-CSS 7 points 100 100 90 80 58% 90 70 60 80 50 40 30 70 20 10 60 0 0 2 4 6 8 12 16 20 24 28 2 4 6 8 12 16 20 24 Weeks Weeks 78 fewer days 80% reduction Guideline Eligibility for SRT NT-proBNP spent SRT-eligible from baseline to Wk 24 100 1000 80 800 60 600 40 400 20 200 Aficamten 0 Placebo 0 2 4 6 8 12 16 20 24 28 0 2 4 6 8 12 16 20 24 28 Washout Weeks Number of patients Weeks Aficamten 139 141 141 139 139 139 137 139 136 135 Aficamten is an investigational drug and is not approved by any regulatory agency. Its safety and efficacy have not been established. Error bars are 95% CI Placebo 138 138 139 136 137 135 135 137 134 135 Maron M. “Aficamten for the Treatment of Symptomatic Obstructive Hypertrophic Cardiomyopathy”. ESC Heart Failure 2024. 20 Proportion of patients with ≥1 Proportion of Patients NYHA FC improvement (%) SRT Eligible (%) NT-proBNP (ng/L) Geometric Mean (95% CI) KCCQ–CSS
SEQUOIA-HCM: Responder Analysis Significant improvement in exercise capacity and symptoms in composite responder endpoint Aficamten Placebo n=142 n=140 ≥1.5 mL/kg/min increase in pVO and ≥1 NYHA FC improvement 2 or 60 (42) 19 (14) ≥3.0 mL/kg/min increase in pVO and no worsening of NYHA FC, n (%) 2 ≥1.5 mL/kg/min increase in pVO and ≥1 NYHA class improvement 44 (31) 9 (6) 2 ≥3.0 mL/kg/min increase in pVO and no worsening of NYHA class 37 (26) 13 (9) 2 Both ≥3.0 mL/kg/min increase in pVO and ≥1 NYHA class improvement 21 (15) 3 (2) 2 Common rate difference vs placebo 28.7 (95% CI) (18.8, 38.6) P value <0.0001 Aficamten is an investigational drug and is not approved by any regulatory agency. Its safety and efficacy have not been established. Maron M. “Aficamten for the Treatment of Symptomatic Obstructive Hypertrophic Cardiomyopathy”. ESC Heart Failure 2024. 21
SEQUOIA-HCM: Safety Data Placebo Aficamten Event, n (%) (n=140) (n=142) Overall AEs 99 (70.7) 105 (73.9) Headache 10 (7.1) 11 (7.7) Hypertension 3 (2.1) 11 (7.7) Palpitations 4 (2.9) 10 (7.0) AEs with ≥5% incidence Upper respiratory infection 12 (8.6) 9 (6.3) COVID-19 9 (6.4) 8 (5.6) Dyspnea 8 (5.7) 8 (5.6) There were no serious adverse SAEs 13 (9.3) 8 (5.6) cardiovascular Cardiac AEs 21 (15.0) 24 (16.9) events associated with aficamten Discontinuations 4 (2.9) 5 (3.5) treatment in SEQUOIA-HCM New-onset AF 1 (0.7) 1 (0.7) Appropriate ICD shock 1 (0.7) 0 a LVEF <50% by core laboratory 1 (0.7) 5 (3.5) Dose reduction based on 1 (0.7) 7 (4.9) site-read LVEF <50% a 1 placebo- and 1 aficamten-treated patient overlap with dose reduction based on site-read LVEF <50%. Aficamten is an investigational drug and is not approved by any regulatory agency. Its safety and efficacy have not been established. AE, adverse event; SAE, serious adverse event. Coats CJ. Dosing and Safety Profile of Aficamten in Symptomatic Obstructive Hypertrophic Cardiomyopathy. ESC Heart Failure 2024. 22
SEQUOIA-HCM: Change in LVEF Modest reduction in LVEF in patients on aficamten resulted in large reductions in LVOT-G Distribution of Categorical Changes in Core Laboratory Mean Change in Core Laboratory LVEF Over 24 Weeks LVEF from Baseline to Week 24 Placebo corrected 100 Washout ΔLVEF = -4.8% Aficamten Decline ≥20% Placebo Decline 75 ≥15% to <20% Decline ≥10% to <15% 50 Decline ≥5% to <10% Aficamten (core) Decline 25 Aficamten (site) ≥0% to <5% Placebo (core) Increase Placebo (site) >0% 0 0 2 4 6 8 12 16 20 24 28 0 10 20 30 40 50 60 Study visit (Week) Patients (%) Aficamten is an investigational drug and is not approved by any regulatory agency. Its safety and efficacy have not been established. Coats CJ. Dosing and Safety Profile of Aficamten in Symptomatic Obstructive Hypertrophic Cardiomyopathy. ESC Heart Failure 2024. 23 Mean LVEF (%) LVEF change category
SEQUOIA-HCM: Low Incidence of LVEF <50% 5 (3.5%) of patients on aficamten had LVEF <50% determined by the core laboratory Site Interpreted Core Laboratory • No treatment interruptions occurred LVEF <50% LVEF <50% o 1 Analysis • No heart failure was experienced by any aficamten-treated patient with LVEF <50% a 1àaficamten by either core laboratory or site 1à placebo interpreted b 6 à aficamten 4 à aficamten 0 à placebo 0 à placebo • All aficamten patients with LVEF <50% were reversible a COVID-19 infection preceded LVEF <50% based on both core and site laboratory assessments. b Did not undergo dose adjustment (3.5%) Aficamten is an investigational drug and is not approved by any regulatory agency. Its safety and efficacy have not been established. Coats CJ. Dosing and Safety Profile of Aficamten in Symptomatic Obstructive Hypertrophic Cardiomyopathy. ESC Heart Failure 2024. 24
SEQUOIA-HCM: Low Overall Incidence of LVEF <50% Core lab LVEF was prespecified source for statistical analyses LVEF <50% assessed at 3.5% by core lab and 4.9% by site Prespecified Analysis Lowest Matching Matching Study Week NT-proBNP, Down- Age, y, Aficamten NYHA Next Visit BL Core LVEF, % With Lowest Core LVEF Site LVEF KCCQ-CSS Change from BL, Titration, Site LVEF Sex Dose, mg/d Class LVEF Core Core LVEF ng/dL mg % % % Core Lab Only LVEF <50% 30 M 20 65 8 48 62 1 +21 −535 N/A 56 65 4 aficamten patients 57 F 5 56 24 2 +14 −372 N/A 51 NR 46 60 72 F 15 80 20 48 52 1 +5 −403 N/A 52 51 57 F 20 84 16 1 +12 −921 N/A 72 68 43 59 Both Core & Site- 75 F Placebo 53 6 48 45 3 +29 −291 N/A 50 51 Read LVEF <50% 72 F * 15 63 16 2 +14 111 15 to 10 55 51 34 49 1 aficamten patient 1 placebo patient Lowest Site Matching Matching Study Week NT-proBNP, Down- Age, y, Aficamten NYHA Next Visit BL Core LVEF, % With Lowest KCCQ-CSS Change from Titration, LVEF Core LVEF Site LVEF Sex Dose, mg/d Class LVEF Core Site LVEF BL, ng/dL mg % % % 41 M 20 70 16 47 59 2 +2 −1597 20 to 15 54 50 Site-Read Only 52 M 20 69 16 1 +25 −712 20 to 15 60 50 46 51 76 F 15 87 16 48 53 3 +22 −44 15 to 10 52 50 LVEF <50% 59 M 15 77 12 2 +10 −1482 15 to 10 60 55 6 aficamten patients 48 70 54 M 15 76 8 1 +31 −162 15 to 10 60 54 49 72 66 M 20 76 20 45 53 3 +8 −83 20 to 15 61 60 * COVID-19 infection preceded LVEF <50% based on both core and site laboratory assessments. NR = not recorded, site LVEF were not obtained following Week 24 per protocol Aficamten is an investigational drug and is not approved by any regulatory agency. Its safety and efficacy have not been established. Coats CJ. Dosing and Safety Profile of Aficamten in Symptomatic Obstructive Hypertrophic Cardiomyopathy. ESC Heart Failure 2024. 25
Implementation of Dosing in Real-World Setting (FOREST-HCM) Low incidence of LVEF <50% in patients with oHCM treated with aficamten N = 282 N = 267 5% 5% 4% 4.2% 4% 3% 3% 3.0% 2.8% 2% 2% 1% 1% 1 patient in common 0% 0% Core Lab Site Site ü No treatment interruptionsü No treatment interruptions ü No heart failure eventsü No heart failure events ü All reversibleü All reversible ü Great majority of patients on highest dosesü Great majority of patients on highest doses Aficamten is an investigational drug and is not approved by any regulatory agency. Its safety and efficacy have not been established. SEQUOIA-HCM Source: Coats CJ. Dosing and Safety Profile of Aficamten in Symptomatic Obstructive Hypertrophic Cardiomyopathy. ESC Heart Failure 2024. FOREST-HCM Source: Data on file – data cut 15 Apr 24 26 Placebo-corrected Incidence LVEF <50% Incidence LVEF <50%
SEQUOIA-HCM: Conclusions Trial underscores potential clinical efficacy & safety of aficamten in patients with symptomatic oHCM • Patients treated with aficamten observed to have: • Clinically meaningful improvements in exercise capacity (pVO ), consistent 2 across all prespecified subgroups • Significant reduction in the burden of limiting symptoms based on improvement in KCCQ-CSS and NYHA Functional Class • Aficamten was generally well-tolerated with low frequency of LVEF <50%, all asymptomatic, with no treatment interruptions and no instances of worsening HF • Functional & symptomatic improvements associated with benefits as early as 2 weeks; remained consistent & durable throughout treatment period: • Substantial relief from resting and provocable LVOT obstruction observed • Large reductions in cardiac biomarker NT-proBNP observed • Considerable reduction in the number of patients eligible for SRT observed • Treatment effects were reversible within the 4-week washout period Aficamten is an investigational drug and is not approved by any regulatory agency. Its safety and efficacy have not been established. Maron M. “Aficamten for the Treatment of Symptomatic Obstructive Hypertrophic Cardiomyopathy”. ESC Heart Failure 2024. Coats CJ. Dosing and Safety Profile of Aficamten in Symptomatic Obstructive Hypertrophic Cardiomyopathy. ESC Heart Failure 2024. Lewis G. Enhancing Exercise Response in Obstructive Hypertrophic Cardiomyopathy. ESC Heart Failure 2024. 27
Preparing for Regulatory Submissions to FDA, EMA • Participated in two meetings with FDA in Q1 2024 • Type B meeting with FDA to occur in Q2 2024 2024 • Meetings with EMA in Q2 2024 • Expect to submit NDA to FDA in Q3 2024 and Positive Results from MAA to EMA in Q4 2024: development of all SEQUOIA-HCM modules underway and manufacturing activities on track Aficamten is an investigational drug and is not approved by any regulatory agency. Its safety and efficacy have not been established. 28
Aspirational Profile of Aficamten & Results from SEQUOIA-HCM Inform Potential REMS REMS Existing Aficamten Aspirational Profile Potential Unique REMS Challenges • Rapid onset • Rapid reversibility • Speed to optimal dose Potential for: Echo frequency • SEQUOIA-HCM: No treatment interruptions due to low LVEF Echo monitoring during titration • SEQUOIA-HCM: No instances of as early as 2 weeks, enabling worsening HF titration to max dose of 20 mg in 6 weeks • Predictable dose response Dosing window • Stable over time Up-titration after each echo based on clinical judgement • No teratogenicity • No clinically meaningful P450 liabilities Flexible echo window for dose DDI monitoring • All background therapies & combinations titration and maintenance have been tested in clinical trials • No QTc liability 29
Few Dose Reductions Occurred During Maintenance FOREST-HCM data cut as of September 15, 2023 Dose Titration Phase Maintenance Phase Down-titration triggered 0.5% • 579 monitoring echocardiograms • No treatment-related LVEF <50% completed* in oHCM patients during the titration period • None with LVEF <40% requiring • Of the 94 patients having completed treatment interruption the titration period, ~2/3 are receiving 15 and 20 mg qd Monitoring • 3 patients (0.5%) with LVEF <50% Echocardiogram • Approximately 30% of patients have • Two asymptomatic patients reduced doses or discontinued (LVEF of 47% and 49%) resulting 99.5% - no change in per-protocol dose reduction background therapy at the discretion of the treating physician • One patient with atrial fibrillation (unrelated) and LVEF of 47% and/or request from the patient Target dose defined as achieved if • All 3 patients are currently Valsalva LVOT-G ≤ 30 mmHg or no dose receiving aficamten with apparent change for 2 consecutive visits relief from obstruction, symptoms & improved biomarkers Aficamten is an investigational drug and is not approved by any regulatory agency. Its safety and efficacy have not been established. 30
Ongoing Clinical Trials of Aficamten Pivotal Phase 3 of aficamten as Pivotal Phase 3 clinical Clinical trial in a pediatric Open-label extension monotherapy vs. metoprolol trial in nHCM population clinical study in HCM as monotherapy in oHCM Aficamten is an investigational drug and is not approved by any regulatory agency. Its safety and efficacy have not been established. 31
Cytokinetics Poised to Compete in the Specialty Cardiology Business Potential for high return on investment Broad Cardiology Specialty Cardiology Example Therapies Heart failure, cholesterol, blood thinner HCM, TTR amyloidosis Prescribers Broad: Cardiologists, PCPs (50K+) Concentrated: Subset of cardiologists (~10K) ROI / Prescriber Limited High Distribution Retail Limited, specialty distributor Customer-Facing Reps Entry level Highly experienced Support Services Standard: Affordability / copay High-touch: Financial, education, journey Managed Care Competitive/high rebates Managed to label Diagnosis High awareness and diagnosis rate Limited awareness with high % undiagnosed HCP – Rep Interactions Brief features/benefits Comprehensive broad-based discussion 32
Market Research Shows Aficamten May Achieve High Share & Grow Category oHCM CMI Preference Shares in • Potential target product profile for aficamten Eligible Patient Population* interest creates share opportunity in newly treated CMI patients • Aficamten could also be expected to expand the total CMI market • Key attributes that may drive preference include the potential for: • LVOT gradient reduction Aficamten • Change in NYHA Functional Class >60% • Pharmacodynamics/LVEF maintenance • Change in KCCQ • Absence of DDI n=443 Survey results are based on the aspirational profile of aficamten and if approved, the actual profile could vary materially. Source: Aficamten Impact of Product Attributes on Product Preference Share n=443 cardiologists, Quantitative research including conjoint - Cogent Aficamten is an investigational drug and is not approved by any regulatory agency. Its safety and efficacy have not been established. 33 Patient Share
If Aficamten is Approved, Expect Majority of CMI-Eligible Patients Available at Launch Diagnosis of HCM anticipated to grow 5x the rate of the general U.S. population US HCM Patients (in ‘000) Illustrative Potential 1,2 Potential 500K nHCM Launch oHCM Launch >90% >80% CMI-Eligible patients available 1 300K Projected Diagnosed HCM Patients 3 (5x the growth rate of the US population) Symptomatic o/nHCM Patients 3 (Considered for CMI) >$5B Potential Potential CMI Use: 25-40% of 3 US Market diagnosed, symptomatic HCM patients 1. DoF: SHA; Symphony PTD (Patient Transaction Data): Includes patients diagnosed since 2016 and having any HC transaction in the claims data universe in the last year June 2022-May 2023); https://www.ajconline.org/article/S0002-9149(21)00783-9/fulltext; CYTK is forecasting an average growth rate of 5% over the coming decade; 2. Butzner et al 2021 estimated a 8% growth rate in diagnosed HCM patients between 2013-2019 3. Internal forecasts Aficamten is an investigational drug and is not approved by any regulatory agency. Its safety and efficacy have not been established. Projections and forecasts for illustration 34 HCM Patients
Cardiologists Located in Concentrated Geographic Clusters Across the US ~75% of the HCM patient volume is treated by ~10,000 cardiologists Geographic Distribution of HCM Patients HCM Patient Concentration by Cardiologist 100% 90% 80% 70% 60% 50% 40% 30% 20% 10% 0% 7,000 10,000 30,000 … Note: includes only patients who are treated by a cardiologist - not all patients see a cardiologist; sample of 67K HCM patients Source: Symphony PTD (Patient Transaction Data); mapping of HCPs to HCOs using Definitive Healthcare Data 2023 and 7/2023 mapping; Patient volume by dominant Cardiologist Location 7/2023 Aficamten is an investigational drug and is not approved by any regulatory agency. Its safety and efficacy have not been established. 35
Gated Build of Commercial Infrastructure Majority of spending to occur closer to potential approval in 2025 2/3 of hiring to occur at-approval Key activities after SEQUOIA-HCM readout Continued insight generation Market access strategy validation Commercial leadership Pricing strategy finalization Marketing Distribution approach HEOR Payer engagement Patient services Brand strategy evolution 1/3 of hires Access & distribution pre-approval Customer account identification Field operations Launch campaign development Commercial learning & Customer Experience development Payer Pre-approval Information Exchange 2/3 of hires at approval Sales force planning Sales team leadership Data & Technology Infrastructure build Omnichannel execution Sales representatives Market development rollout Initiated upon FDA approval Media purchases Patient support programs Peer to peer engagement Aficamten is an investigational drug and is not approved by any regulatory agency. Its safety and efficacy have not been established. HCP Omnichannel launched 36
Omecamtiv Mecarbil 37
Omecamtiv Mecarbil: Mechanism of Action Omecamtiv mecarbil shifted equilibrium in favor of the pre-powerstroke state “More hands pulling on the rope” Before Omecamtiv Mecarbil After Omecamtiv Mecarbil OM Mechanochemical P i ADP domain Pre-Powerstroke State Actin sliding Actin sliding Malik, et al. Science 2011; 1439-1443 Planelles-Herrero, et al. Nature Comm 2017; 1-10 Shen et al, Circ HF, July 2010, 522-527 Teerlink, et al. JACC-HF 2020; 329-340 Omecamtiv mecarbil is an investigational drug and is not approved by any regulatory agency. Its safety and efficacy have not been established. 38
GALACTIC-HF: Clinical Trial Overview Phase 3 clinical trial Event-driven clinical trial; 8256 patients randomized in 35 countries at 944 clinical trial sites Chronic HFrEF Patients Currently hospitalized for Inpatients Omecamtiv mecarbil + Standard HF Therapy primary reason of HF (25% of enrollment) History of hospitalization or ER/ED admission for a primary History of Hospitalization Placebo + Standard HF Therapy reason of HF within 1 year or ER/ED visit for a primary (75% of enrollment) reason of HF within 1 year Study Visits D1 W2 W4 W6 W8 W12 W24 W36 W48 Q16W Omecamtiv mecarbil is an investigational drug and is not approved by any regulatory agency. Its safety and efficacy have not been established. 39 Screening Randomization 1:1 End of Study
Primary Composite Endpoint 50 Placebo HR = 0.92 45 (95% CI, 0.86–0.99) Omecamtiv 40 P = 0.025 mecarbil 35 CV Death 30 HR = 1.01 (95% CI, 0.92–1.11) 25 P = 0.86 20 Omecamtiv 15 mecarbil 10 5 0 18 0 6 12 24 30 36 Months (30 days) since randomization Patients at risk, n Placebo 4112 3310 2889 2102 1349 647 141 OM 4120 3391 2953 2158 1430 700 164 Time to first HF event or CV death Omecamtiv mecarbil is an investigational drug and is not approved by any regulatory agency. Its safety and efficacy have not been established. 40 Cumulative incidence, %
Benefit Observed to Increase As Baseline LVEF Decreased Incidence of Primary Composite Endpoint Relative Treatment Effect on Primary Endpoint 60 1.2 50 Placebo 40 Treatment 1.0 Effect 30 0.8 Omecamtiv mecarbil 20 0.6 2414 patients 5,842 patients 10 10 15 20 25 30 35 10 15 20 25 30 35 Ejection fraction (%) Ejection fraction (%) Baseline ≤ median (28%) 0.84 (0.77, 0.92) Pre- LVEF > median (28%) 1.04 (0.94, 1.16) specified Subgroup Interaction P-value = 0.004 ARR = Absolute Risk Reduction. RRR = Relative Risk Reduction. Teerlink JR., Diaz R., Felker GM., et al. Effect of Ejection Fraction on Clinical Outcomes in Patients treated with Omecamtiv Mecarbil in GALACTIC-HF. JACC. 2021 Omecamtiv mecarbil is an investigational drug and is not approved by any regulatory agency. Its safety and efficacy have not been established. 41 Incidence Rate (per 100 py) Treatment Effect (Ratio)
In Post-Hoc Analysis, Greater Benefit in Patients with Worsening HF Omecamtiv mecarbil is an investigational drug and is not approved by any regulatory agency. Its safety and efficacy have not been established. 42
Safety Results in Low LVEF Subgroup Were Observed to Continue Incidences of SAEs, ventricular arrhythmias, & cardiac ischemic events were similar LVEF ≤28% Overall Population Incidence of stroke was lower with omecamtiv mecarbil Omecamtiv Omecamtiv Mecarbil Placebo Mecarbil Placebo N=4110 N=4101 N=2208 N=2236 % % % % Serious adverse events 57.7 59.4 58.8 61.9 Adverse events Ventricular tachyarrhythmia (narrow SMQ) 7.1 7.4 8.0 8.2 Torsade de pointes/QT prolongation (SMQ) 4.3 4.8 5.2 5.8 Serious adverse ventricular arrhythmia requiring Rx 2.9 3.1 3.4 3.6 Adjudicated major cardiac ischemic event 4.9 4.6 4.6 4.2 Myocardial infarction 3.0 2.9 3.0 2.9 Hospitalized for unstable angina 0.6 0.3 0.4 0.2 Coronary revascularization 2.8 2.9 2.6 2.5 Adjudicated stroke 1.6 2.8 2.1 2.6 GALACTIC-HF CSR Table 14.3.4.5.27 Omecamtiv mecarbil is an investigational drug and is not approved by any regulatory agency. Its safety and efficacy have not been established. 43
Omecamtiv Mecarbil: Current Status Received CRL from FDA Withdrew MAA from EMA GALACTIC-HF not sufficiently Withdrew the MAA from the EMA persuasive to establish substantial based on feedback from the CHMP evidence of effectiveness for indicating that the Committee will reducing the risk of heart failure not be able to conclude that the events and cardiovascular death in benefits outweigh the risks on the adults with chronic HFrEF basis of the results from GALACTIC-HF alone Omecamtiv mecarbil is an investigational drug and is not approved by any regulatory agency. Its safety and efficacy have not been established. 44
Omecamtiv Mecarbil: HFrEF Epidemiology Heart Failure Prevalence All HF Patients 2023, US 8.0 18% 6.0 4.0 7.1 7.1 7.1 2.0 0.0 Tsao 2023 AHA Racine 2022 CVrg Bionest 2021 LVEF <30% LVEF >30% 7.1M (2023) Circ Heart Fail. 2012;5:720-726 REAL HFrEF Study 2021 Omecamtiv mecarbil is an investigational drug and is not approved by any regulatory agency. Its safety and efficacy have not been established. 45 HF Prevalence (M)
Omecamtiv Mecarbil: SOC Not Addressing Needs of Patients with EF <30% Proposed Patient Type for Omecamtiv Mecarbil Physician Experience with HFrEF Treatment • EF <30% • Not responding to current Physicians have treatment options, recently many tools in their They’re balancing They’re still looking hospitalized toolbox –ACEs, maximally tolerated for something more ARBs, Entresto and treatment with side to treat patients with • Patients with renal insufficiency / SGLT2s are effects and safety severely reduced LVEF hypotension / elevated NT-pro BNP standard of care • Have contraindications limiting necessary SoC dose increases, e.g. low BP or renal dysfunction • Higher NYHA grade Omecamtiv mecarbil is an investigational drug and is not approved by any regulatory agency. Its safety and efficacy have not been established. 46
CK-586 47
CK-586: Distinct Mechanism of Action from Aficamten “Fewer hands pulling on the rope” Before CK-586 After CK-586 Mechanochemical CK- domain 586 ATP Post-Powerstroke State Actin sliding Actin sliding CK-586 is an investigational drug and is not approved by any regulatory agency. Its safety and efficacy have not been established. 48
Heart Failure with Preserved Ejection Fraction (HFpEF) 1 Despite broad use of standard treatments and advances in care, the prognosis for patients with heart failure is poor ~50% ~75% ~84% 8.5 million Americans will have HF patients have HFpEF patients will HFpEF patients will 3 2 heart failure by HFpEF & die within five be rehospitalized 2 2030 prevalence of HFpEF years of initial 2,4 2 is increasing hospitalization 1. Jhund PS, MacIntyre K, Simpson CR, et al. Long-Term Trends in First Hospitalization for Heart Failure and Subsequent Survival Between 1986 and 2003. Circulation. 2009;119:515-523. 2. Bozkurt B, Ahmad T, Alexander KM, Baker WL, Bosak K, Breathett K, Fonarow GC, Heidenreich P, Ho JE, Hsich E, Ibrahim NE, Jones LM, Khan SS, Khazanie P, Koelling T, Krumholz HM, Khush KK, Lee C, Morris AA, Page RL 2nd, Pandey A, Piano MR, Stehlik J, Stevenson LW, Teerlink JR, Vaduganathan M, Ziaeian B; Writing Committee Members. Heart Failure Epidemiology and Outcomes Statistics: A Report of the Heart Failure Society of America. J Card Fail. 2023 Oct;29(10):1412-1451. doi: 10.1016/j.cardfail.2023.07.006. Epub 2023 Sep 26. PMID: 37797885; PMCID: PMC10864030. 3. Dunlay SM, Roger VL, Weston SA, Jiang R, Redfield MM. Longitudinal changes in ejection fraction in heart failure patients with preserved and reduced ejection fraction. Circ Heart Fail. 2012 Nov;5(6):720-6. doi: 10.1161/CIRCHEARTFAILURE.111.966366. Epub 2012 Aug 30. PMID: 22936826; PMCID: PMC3661289. 4. Yancy CW, Jessup M, Bozkurt B, et al. 2013 ACCF/AHA Guideline for the Management of Heart failure: A Report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Circulation. 2013;128:e240-e327. 49
CK-586: Shallow In Vivo Concentration-Response CK-586 will have a shorter half-life in humans than aficamten Pharmacodynamic window Fractional shortening IC /IC ratio 50 10 mavacamten 2.8x aficamten 9.9x CK-586 9.3x IC : plasma concentration at 10% relative reduction in fractional shortening 10 IC : plasma concentration at 50% relative reduction in fractional shortening 50 Compound half-life Actual Predicted in humans aficamten ~3 days 2.8 days CK-586 TBD 15 hours Aficamten CK-4021586 (3 – 30 mg/kg, PO) CK-586 is an investigational drug and is not approved by any regulatory agency. Its safety and efficacy have not been established. 50
Phase 1 Data Support Advancement to Phase 2 Clinical Trial Full data to be presented at a medical congress in 2H 2024 Phase 1 Design Key Findings • Pharmacodynamics were evaluated using echocardiography and consistent with expectations • 7 SAD cohorts (10 mg to 600 mg) comprised of 10 participants each • CK-586 was generally safe and well- tolerated with linear PK • 2 MAD cohorts (100 and 200 mg once daily) comprised of 10 participants each • No series adverse events were observed • Stopping criteria were not met CK-586 is an investigational drug and is not approved by any regulatory agency. Its safety and efficacy have not been established. 51
Corporate Profile 52
Myosin Platform Drives Multiple Data Milestones and Potential Approvals Potential Results Aficamten Aficamten FDA Approval oHCM SEQUOIA-HCM Potential For illustrative purposes only Results Approval Enhancing shareholder Aficamten Emerging value Pipeline MAPLE-HCM Results Aficamten Aficamten oHCM SEQUOIA-HCM Potential Aficamten Results Approval CK-586 oHCM Phase 3 First-line Aficamten Aficamten Results Potential Aficamten Emerging oHCM SEQUOIA-HCM MAPLE-HCM Label Exp. Potential Pipeline Results Results Approval Aficamten Emerging Aficamten MAPLE-HCM CK-586 Pipeline nHCM Results Phase 2 Aficamten Potential oHCM Results CK-586 Approval Aficamten First-line Aficamten Phase 3 CK-586 ACACIA-HCM oHCM Results Potential Phase 3 First-line Label Exp. Results Results Potential Label Exp. Aficamten Aficamten CK-586 CK-586 nHCM nHCM Phase 2 Phase 2 2027-2028 Potential Potential Results Results Aficamten Aficamten Approval Approval ACACIA-HCM ACACIA-HCM Results Results 2024 2025-2026 53
Balance Sheet & Financial Guidance Approximately 2 years of cash runway based on 2024 guidance* 2024 Condensed Balance Sheet in millions As of 3/31/2024 Total $634.3 Cash and investments 2024 Financial Guidance Accounts receivable $0.8 $68.0 PPE • GAAP Operating (R&D and G&A) $535 to $555 million Leased assets $78.2 Expense: $26.8 Other assets • Non-cash expenses included in Total Assets $808.1 $115 to $105 million GAAP Operating Expense**: Convertible Debt, net $549.8 $390.2 Liability related to sale of future royalties • Operating Expense (R&D and G&A) $420 to $450 million Lease liability $136.8 excluding non-cash expenses $127.4 Other liabilities Total Liabilities $1,204.2 Working capital $549.8 • Expected Net Cash Utilization***: $390 to $420 million Accumulated deficit ($2,247.9) Stockholders’ deficit ($396.2) Wtd Avg Basic Shares Outstanding (million) 101.9 * Including up to $175M we expect to be available to us under our loan agreement with Royalty Pharma, upon satisfaction of conditions. **Non-cash expenses included in GAAP Operating Expenses are comprised of stock-based compensation and depreciation. Non-cash expense is a non-GAAP financial measure that should be considered as supplemental information regarding our operations and should not be considered without also considering our results prepared in accordance with U.S. GAAP. It should not be considered as a substitute for, or superior to, our U.S. GAAP results. We believe non- cash expenses is a relevant and useful operational measure as our management uses it to budget and plan for the business and also useful to investors because similar measures are used by securities analysts, investors and others in their evaluation of companies in similar industries. Non-cash expense as we present it may not be comparable with similarly titled operational measures used by other companies. Our expectations regarding non-cash expenses are based on information currently available to us, but are forward-looking statements subject to change. ***We define “Net Cash Utilization” as change in cash, cash equivalents and investments year over year. 54
Planned 2024 Milestones Af Aic fica am mtt ee nn CK-586 Share full data from Phase 1 study Complete enrollment of MAPLE-HCM Submit NDA to FDA in Q3 2024 and of CK-586 in 2H 2024 MAA to EMA in Q4 2024 in Q3 2024 Initiate Phase 2 study Continue enrollment in ACACIA-HCM of CK-586 in Q4 2024 Continue enrollment of CEDAR-HCM In 2024 in 2024 Pre-Clinical Development & Ongoing Research Begin Phase 1 study of aficamten in Initiate clinical development with healthy Japanese volunteers another muscle-directed in Q2 2024 compound in 2024 Aficamten and CK-586 are investigational drugs and have not been approved. Their safety and efficacy have not been established. 55
thank you