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

 Extensive clinical data  7 trials in HFrEF patients;

• ver 3,000 patients

 “BEST” Phase 3 trial

• 2,708 patients
• 1,040 pt DNA sub-study

 74% reduction in incidence

• f new onset AF in patients

with most responsive genotype

 β-blocker with unique

mechanism of action

 Well tolerated with

excellent safety profile

 Enhanced clinical

response based on genotype

 Most responsive

genotype present in 50%

• f U.S. population

 Phase 2B/3 adaptive

design, superiority trial

 Genotype-defined HFrEF

population

 Phase 2B DSMB interim

efficacy analysis outcome anticipated Sept. 2017

 Potentially pivotal trial, if

advanced to Phase 3

Clinical Unique Compound GENETIC-AF trial

GencaroTM

Potentially the first genetically-targeted treatment for atrial fibrillation (AF)

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Atrial Fibrillation (AF) – An Epidemic CV Disease

Revenue ($B)

Global Atrial Fibrillation Market - Estimated $12.5 Billion by 20201

• AF is the most common sustained cardiac arrhythmia - affects ~5.2 million (2015) Americans2
• AF is considered an epidemic cardiovascular (CV) disease based on the pace of increase in

incidence in the U.S. and industrialized countries3

• 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 2 4 6 8 10 12 14 2015 2020

AF in HFREF – An Unmet Medical Need

• A top unmet need for AF treatment are pharmacotherapies for patients

with comorbid chronic heart failure1

• 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.

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Gencaro (bucindolol hydrochloride)

Compound

 β-blocker/vasodilator – well characterized drug class  β-blockers target cardiac myocytes to reduce adverse β1-

adrenergic signaling that causes cardiac chamber remodeling

 Well characterized safety profile  IP protection through 2030

Unique MOA

 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 – β1- and α2c  Optimal genotype is ADRB1 Arg389Arg – present in 50% of U.S. population  ARCA & LabCorp jointly developed companion diagnostic test

CN O OH N H NH2+ Cl

Phase 3 BEST trial: Prevention of AF

0.70 0.75 0.80 0.85 0.90 0.95 1.00 6 12 18 24 30 36 42 48

Months After Randomization

Placebo Bucindolol

Entire cohort (Pts in SR @ Bsl) (n = 2392; 190 events )

Hazard Ratio = 0.59 (0.44 – 0.79) P-value = 0.0004

0.70 0.75 0.80 0.85 0.90 0.95 1.00 6 12 18 24 30 36 42 48

Months After Randomization

Placebo Bucindolol

BEST DNA substudy (Pts in SR @ Bsl) (n = 925; 80 events )

Hazard Ratio = 0.57 (0.36 – 0.90) P-value = 0.014

Entire cohort vs. DNA sub-study

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0.70 0.75 0.80 0.85 0.90 0.95 1.00 6 12 18 24 30 36 42 48 Probability of Event-Free Survival Months After Randomization Placebo Bucindolol

Phase 3 BEST trial: Prevention of AF (2)

BEST adrenergic receptor polymorphism substudy

b1389 Arg/Arg (n = 441; 36 events)

Risk reduction 74% 0.70 0.75 0.80 0.85 0.90 0.95 1.00 6 12 18 24 30 36 42 48 Probability of Event-Free Survival Months After Randomization Placebo Bucindolol

Hazard Ratio = 1.01 (0.56 – 1.84) P-value = 0.969

b1389 Gly carriers (n = 484; 44 events)

No risk reduction

Interaction p = 0.008

8 Hazard Ratio = 0.26 (0.12 – 0.57) P-value = 0.0003

b1389 Arg/Arg (n = 441; 36 events)

Hazard Ratio = 0.26 (0.12 – 0.57) P-value = 0.0003 Risk reduction 74% Interaction p = 0.008 0.70 0.75 0.80 0.85 0.90 0.95 1.00 6 12 18 24 30 36 42 48 Probability of Event-Free Survival Months After Randomization Placebo Bucindolol Aleong et al, Circulation 124: A10438, 2011

Beta-blockers currently used

• ff-label. In a meta-analysis of

Phase 3 HF trials including ~12,000 randomized patients, there was a 27% average reduction in incidence of new

• nset AF in heart failure

where new onset AF was reported.1

1 - Abi Nasr I et al, EHJ 28: 457–462, 2007

Prevention of new onset AF

BEST adrenergic receptor polymorphism substudy Beta-blockers

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Metoprolol & Carvedilol not influenced by ADRB1 Arg389Gly

Sehnert AJ, et al. JACC 52:644-651, 2008

No effect of b1-389 Arg/Gly polymorphism (ADRB1-389)

• n therapeutic response to

metoprolol CR/XL (n=361), or carvedilol (n=276) (Panel B)

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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

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Gencaro for Atrial Fibrillation in Genotype- Defined Heart Failure Population AF in HFREF

No FDA approved drugs for this indication

U.S. FDA Fast Track Designation (April 2015)

LVEF <0.50, HFrEF (not Class IV); current/recent Hx of persistent or paroxysmal Sx AF (<180 days) Bucindolol Toprol XL ECV @ 3 wks if AF present

Phase 2B Interim Analysis: DSMB Evaluation of AF endpoints, AF burden, hospitalizations and ACM

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Trial 1° Endpoint: Time to 1st Symptomatic AF/AFL or ACM during 24 week follow-up Randomization: ADRB1 Arg389Arg genotype

Target trial sites: U.S, Canada & Europe Phase 2B ~ 75 Phase 3 ~ 140 1:1 Phase 2B Phase 3 Total (N ~ 620)

24-week Follow-up for 1EP + Blinded Treatment Extension Period

GENETIC-AF: Phase 2BPh 3 Adaptive Design Superiority Trial

Bucindolol vs. Toprol XL, Prevention of Recurrent AF in HFrEF Patients with the b1389 Arg/Arg Genotype

Companion Diagnostic: Gencaro Test

• Gencaro Test
• Identifies patient ADRB1 ARg389Gly genotype
• LabCorp providing test & services to support GENETIC-AF
• LabCorp obtained FDA Investigational Device Exemption (IDE)
• Laboratory Corporation of American

– World’s leading healthcare diagnostics company – 470,000 tests daily – 50,000 employees worldwide – $9.4 Billion – 2016 Revenues

LabCorp and ARCA have jointly developed the companion diagnostic for Gencaro

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Medtronic Collaboration

• Collaboration
• Measurement of AF burden by means of implanted Medtronic

continuous monitoring devices

• Substudy of patients in Phase 2B and Phase 3
• Medtronic to provide centralized analysis of AF burden
• Medtronic, Inc.

– Global healthcare solutions company – Leader in medical technologies to improve the treatment of chronic diseases, including cardiac rhythm disorders – 88,000 employees – $28.8 Billion – 2016 Revenues – $2.2 Billion – 2016 Research & Development Investment Medtronic and ARCA have an established collaboration on GENETIC-AF trial

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GENETIC-AF Trial: Phase 2B Projected Timeline

 Revised protocol distributed to current and potential clinical trial sites March 2015  FDA Fast Track Designation April  GENETIC-AF Trial Investigators meeting and training May  First trial sites operating under revised protocol May  Approximately 65 clinical trial sites in U.S. & Canada Dec  50 patients enrolled in trial January 2016  75 patients enrolled in trial April  100 patients enrolled in trial August  GENETIC-AF Trial European Investigators meeting and training September  1st European patient randomized October  125 patients enrolled in trial November  150 patients enrolled in trial January 2017  175 patients enrolled in trial March  200 patients enrolled in trial April  Outcome of DSMB Phase 2B Interim Efficacy Analysis September 2017

(Guidance as of April 26, 2017)

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Advance to Pivotal Phase 3 Futility – Stop Trial Complete Phase 2B

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DSMB Interim Analysis Recommendation

GENETIC-AF DSMB Phase 2B Interim Efficacy Analysis

• At least 150 patients with evaluable data; unblinded to DSMB
• Bayesian predictive probability efficacy analysis
• Evaluation of time to recurrent AF or ACM endpoint, ACM, AF burden and

hospitalizations

• Safety
• Update on pretrial assumptions: AF event rate, genotype, screen fail rate

~ 250 total patients ~ 620 total patients (P2 patients included)

Significant & Growing Market Opportunity

Atrial fibrillation market growing at CAGR of 23.5% 2009-20171 ARCA estimates Gencaro AF in HFREF to be a $450M -$900M opportunity

Estimated U.S. Market in 20222

9.0M2 6.3M .7-1.4M 350-700K

Heart failure patients HFREF patients Persistent/paroxysmal AF patients ADRB1 Arg389Arg genotype

18 1- “Atrial Fibrillation Therapeutics – Pipeline Assessment and Market Forecasts to 2017”, Dec 2010 2- GlobalData – “Epicast Report: Chronic Heart Failure – Epidemiology Forecast to 2022”, Jan 2013

Bucindolol Market Exclusivity / Intellectual Property Protection

Hatch-Waxman [5 years from approval] Hatch-Waxman Patent Extension [7.5 years from approval] EU Data Exclusivity [10 – 11 years from EU approval] Bucindolol Patents [use of drug w/ genetic markers]

Potential US Approval

2030*

Worldwide Rights

Bucindolol Patents Issued US – 2010, 2011, 2012 Europe –2010

* Potential exclusivity into 2030 in US & EU based on patent and patent term extension

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Additional Potential Indications

Prior clinical data from cardiovascular endpoints in the 2,708 patient BEST Phase 3 clinical trial indicate Gencaro has potential in additional CV indications in ADRB1 Arg389Arg populations:

• Permanent AF in HFrEF, for rate control and preventing HF events
• Ventricular tachycardia/ventricular fibrillation in HFREF
• HFREF regardless of rhythm
• AF prevention in HFpEF or in normal LV function

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Capital Structure

• Shares outstanding:

9.1 million

• Potentially dilutive securities:

4.3 million

• Fully diluted:

13.4 million

• Net cash (12/31/16):

$23.5 million

• No debt

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Experienced Leadership

Michael R. Bristow, MD, PhD: President /CEO Thomas Keuer: Chief Operating Officer Chris Ozeroff: General Counsel Brian Selby: VP, Finance & Chief Accounting Officer Debra Marshall, MD, FACC: SVP, Medical Affairs Gordon Davis: VP, Clinical Information Systems Chris Dufton, PhD: VP, Clinical Development Sharon Perry: Sr Director, Regulatory Affairs & Quality

Board of Directors

Michael R. Bristow, MD, PhD Robert E. Conway (Chairman) Linda Grais, MD, JD Anders Hove, MD Dan Mitchell Raymond L. Woosley, MD, PhD

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ARCA Investment Opportunity

Late stage genetically-targeted cardiovascular company

• Phase 2B/3 GENETIC-AF trial currently enrolling patients in US, Canada & Europe
• Well-defined development and regulatory pathway
• Funded beyond next major clinical milestone
• Strong collaborations and institutional investors

Large and Growing Market Opportunity

• Estimated $12.5 billion global atrial fibrillation market by 2020
• Significant unmet medical need in AF in HFrEF with no FDA approved treatments
• Gencaro in AF in HFrEF potential annual sales of $450M-$900M in US
• Potentially first genetically-targeted atrial fibrillation treatment

Cardiovascular and Biotech Veterans with Demonstrated Success

• Management team with extensive experience in CV disease, drug development

and corporate execution

• Team previously successful in drug clinical development & regulatory approvals
• Demonstrated ability to drive execution

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ARCA biopharma

April 2017

Pharmacogenetic Precision Medicine for Cardiovascular Diseases