ARCA biopharma Pharmacogenetic Precision Medicine for - PowerPoint PPT Presentation

ARCA biopharma Pharmacogenetic Precision Medicine for Cardiovascular Diseases April 2017

Safe Harbor Statement This presentation contains "forward-looking statements" for purposes of the safe harbor provided by the Private Securities Litigation Reform Act of 1995. These statements include, but are not limited to, statements regarding, the potential that the data from 150 patients will support a recommendation that the GENETIC-AF trial transition to Phase 3, the potential timeline for GENETIC-AF trial activities and related recommendations of the DSMB, potential timing for patient enrollment in the GENETIC-AF trial, the sufficiency of the Company’s capital to support its operations, the potential for genetic variations to predict individual patient response to Gencaro, Gencaro’s potential to treat atrial fibrillation, future treatment options for patients with atrial fibrillation, and the potential for Gencaro to be the first genetically-targeted atrial fibrillation prevention treatment. Such statements are based on management's current expectations and involve risks and uncertainties. Actual results and performance could differ materially from those projected in the forward-looking statements as a result of many factors, including, without limitation, the risks and uncertainties associated with: the Company's financial resources and whether they will be sufficient to meet the Company's business objectives and operational requirements; results of earlier clinical trials may not be confirmed in future trials, the protection and market exclusivity provided by the Company’s intellectual property; risks related to the drug discovery and the regulatory approval process; and, the impact of competitive products and technological changes. These and other factors are identified and described in more detail in ARCA’s filings with the Securities and Exchange Commission, including without limitation the Company’s annual report on Form 10-K for the year ended December 31, 2016, and subsequent filings. The Company disclaims any intent or obligation to update these forward-looking statements. 2

Gencaro TM Potentially the first genetically-targeted treatment for atrial fibrillation (AF) Unique Compound Clinical GENETIC-AF trial  Extensive clinical data  β -blocker with unique  Phase 2B/3 adaptive mechanism of action design, superiority trial  7 trials in HFrEF patients; over 3,000 patients  Well tolerated with  Genotype-defined HFrEF excellent safety profile population  “BEST” Phase 3 trial  Enhanced clinical  Phase 2B DSMB interim - 2,708 patients response based on efficacy analysis outcome - 1,040 pt DNA sub-study genotype anticipated Sept. 2017  74% reduction in incidence  Most responsive  Potentially pivotal trial, if of new onset AF in patients genotype present in 50% advanced to Phase 3 with most responsive of U.S. population genotype 3

Atrial Fibrillation (AF) – An Epidemic CV Disease 14 12 10 Revenue ($B) Global Atrial Fibrillation Market - 8 Estimated $12.5 Billion by 2020 1 6 4 2 0 2015 2020 • AF is the most common sustained cardiac arrhythmia - affects ~5.2 million (2015) Americans 2 • AF is considered an epidemic cardiovascular (CV) disease based on the pace of increase in incidence in the U.S. and industrialized countries 3 • 250,000 - 500,000 new onset AF cases/year in HFREF patients 1 DelveInsight – “Atrial Fibrillation – Market Insights & Drug Sales Forecast - 2020”, May 2016 2 American Journal of Cardiology 2013: 112: 1142- 1147 “Estimates of current and future incidence and prevalence of atrial fibrillation in the U.S. adult population; AHA – “Cardiovascular Disease: A Costly Burden for America” (Jan 2017), page 7 3 Journal of the American Medical Association. 2001; 285(18):237 0-2375 4

AF in HFREF – An Unmet Medical Need • A top unmet need for AF treatment are pharmacotherapies for patients with comorbid chronic heart failure 1 • No FDA approved drugs for this indication • Currently approved antiarrhythmic agents for non-HFREF patients are associated with significant side effects: – Most are contraindicated or have warnings for HFREF • New onset AF markedly worsens HF morbidity & mildly increases mortality • β -blockers approved for HFREF but used off-label for AF have demonstrated only limited efficacy • No agents approved for AF or HFREF have genetically influenced clinical response for arrhythmia events Source(s)/Note(s): 1 – Decision Resources Group, “Atrial Firbrillation , December 2014”, p1 AHA; Atrial Fibrillation, 5/3/07: www.americanheart.org, eMedicine, Atrial Fibrillation, Jan. 2007: http://www.emedicine.com/med/topic184.htm ; Decision Resources, Cardium: Atrial Fibrillation, 2003. 5

Gencaro (bucindolol hydrochloride) Compound  β -blocker/vasodilator – well characterized drug class  β -blockers target cardiac myocytes to reduce adverse β 1- adrenergic signaling that causes cardiac chamber remodeling  Well characterized safety profile  IP protection through 2030 CN H Cl N Unique MOA NH 2 + O OH  Competitive antagonism  Sympatholysis – norepinephrine (NE) lowering  Inverse agonism – inactivation of constitutively active receptors  Other β -blockers lack these last 2 properties Genotype Specific Response  Clinical response differentiated by patient genetic profile  Via 2 specific adrenergic receptor (AR) polymorphisms – β 1- and α 2c  Optimal genotype is ADRB1 Arg389Arg – present in 50% of U.S. population  ARCA & LabCorp jointly developed companion diagnostic test

Phase 3 BEST trial: Prevention of AF Entire cohort vs. DNA sub-study Entire cohort (Pts in SR @ Bsl) BEST DNA substudy (Pts in SR @ Bsl) (n = 2392; 190 events ) (n = 925; 80 events ) 1.00 1.00 0.95 0.95 0.90 0.90 0.85 0.85 Placebo Placebo 0.80 Bucindolol 0.80 Bucindolol 0.75 0.75 Hazard Ratio = 0.57 (0.36 – 0.90) Hazard Ratio = 0.59 (0.44 – 0.79) P-value = 0.014 P-value = 0.0004 0.70 0.70 0 6 12 18 24 30 36 42 48 0 6 12 18 24 30 36 42 48 Months After Randomization Months After Randomization 7

Phase 3 BEST trial: Prevention of AF (2) BEST adrenergic receptor polymorphism substudy b 1 389 Arg/Arg (n = 441; 36 events) b 1 389 Gly carriers (n = 484; 44 events) Interaction p = 0.008 Risk reduction 74% No risk reduction 1.00 1.00 Probability of Event-Free Survival Probability of Event-Free Survival 0.95 0.95 0.90 0.90 0.85 0.85 Placebo Placebo 0.80 0.80 Bucindolol Bucindolol 0.75 0.75 Hazard Ratio = 0.26 (0.12 – 0.57) Hazard Ratio = 1.01 (0.56 – 1.84) P-value = 0.969 P-value = 0.0003 0.70 0.70 0 6 12 18 24 30 36 42 48 0 6 12 18 24 30 36 42 48 Months After Randomization Months After Randomization 8

Prevention of new onset AF BEST adrenergic receptor polymorphism substudy b 1 389 Arg/Arg (n = 441; 36 events) Beta-blockers Risk reduction 74% 1.00 Beta-blockers currently used Probability of Event-Free Survival off-label. In a meta-analysis of 0.95 Phase 3 HF trials including ~12,000 randomized patients, 0.90 there was a 27% average reduction in incidence of new 0.85 Interaction p = 0.008 onset AF in heart failure 0.80 Placebo where new onset AF was reported. 1 Bucindolol 0.75 Hazard Ratio = 0.26 (0.12 – 0.57) P-value = 0.0003 0.70 0 6 12 18 24 30 36 42 48 1 - Abi Nasr I et al, EHJ 28: 457 – 462, 2007 Months After Randomization Aleong et al, Circulation 124: A10438, 2011 9

Metoprolol & Carvedilol not influenced by ADRB1 Arg389Gly No effect of b 1-389 Arg/Gly polymorphism (ADRB1-389) on therapeutic response to metoprolol CR/XL (n=361), or carvedilol (n=276) (Panel B) Sehnert AJ, et al. JACC 52:644-651, 2008 10

Regulatory Strategy Obtain an atrial fibrillation approval in a genotype-defined heart failure population via adaptive design Phase 2B/3 trial of 620 patients • Clearly defined regulatory pathway – Similar endpoints used for most recent AF FDA approvals – Safety profile – well characterized based on prior development – Company has clear understanding of pathway, safety profile and effective trial design • Possibility of approval based on GENETIC-AF (Phase 3), if p<0.01, when submitted with BEST trial data • Second trial may be required if GENETIC- AF p>0.01 • Seeking partners outside of U.S. & Canada 11

U.S. FDA Fast Track Designation ( April 2015) Gencaro for Atrial Fibrillation in Genotype- Defined Heart Failure Population AF in HFREF No FDA approved drugs for this indication

GENETIC-AF: Phase 2B  Ph 3 Adaptive Design Superiority Trial Bucindolol vs. Toprol XL, Prevention of Recurrent AF in HFrEF Patients with the b 1 389 Arg/Arg Genotype LVEF <0.50, HFrEF (not Class IV); current/recent Hx of persistent or paroxysmal Sx AF (<180 days) Randomization: ADRB1 Arg389Arg genotype 1:1 Phase 2B Bucindolol Target trial sites: Toprol XL Phase 3 U.S, Canada & Europe Total (N ~ 620) Phase 2B ~ 75 ECV @ 3 wks if AF present Phase 3 ~ 140 24-week Follow-up for 1EP + Blinded Treatment Extension Period Phase 2B Interim Analysis: DSMB Evaluation of AF endpoints, AF burden, hospitalizations and ACM Trial 1° Endpoint: Time to 1 st Symptomatic AF/AFL or ACM during 24 week follow-up 13