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One Year Follow-Up Results from AUGMENT-HF: A Multicenter Randomized Controlled Clinical Trial of

the Efficacy of Left Ventricular Augmentation with Algisyl-LVR in the Treatment of Heart Failure*

Douglas L. Mann, Randall J. Lee, Andrew J.S. Coats, Gheorghe Neagoe, Dinu Dragomir,

Enrico Pusineri, Massimo Piredda, Luca Bettari, Bridget-Anne Kirwan, Robert Dowling,

Maurizio Volterrani, Scott D. Solomon, Hani N. Sabbah, Andy Hinson, Stefan D. Anker

on behalf of the AUGMENT-HF Investigators

Disclosures: Scientific Advisory Board - Lone Star Heart, miRagen therapeutics, Lilly CorporationConsultant – Bio Control Medical, Cardioxyl, MedtronicGrant Support – NIH

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• Therapeutic options are limited for patients with advanced heart failure who become refractory to conventional pharmacological therapies

• The injection of biomaterials into diseased myocardium has been shown to reduce myofiber stress, LV wall stress, restore LV geometry and improve LV function1,2

• Algisyl® is a medical device that consists of an alginate hydrogel that is injected into the midwall of the LV, where it remains as a permanent implant that is intended to reduce LV wall stress and prevent or reverse the progression of HF

• Results of the AUGMENT-HF 6-month primary endpoint analysis were presented at this meeting in 2014 and published earlier this summer3

Background

1 Sabbah HN, et. al., JACC Heart Fail. 2013;1(3):252-8.2 Lee RJ, et. al, Int J Cardiol. 2015 Jul 2;199:18-24.3 Anker, SD, et. al. Eur Heart J. 2015 Sep 7;36(34):2297-309

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Modified (LVR)Dilated

σ P x R=

2hσ P x R

=2h

R Rh

Mechanism of Action of Algisyl

h

LV Restoration & Laplace’s Law

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Placement of Alginate Hydrogel via a Limited Thoracotomy

LV Restoration with Algisyl

Mean procedure duration 80.5 (±24.9) minutesMean number of implants 15.5 (±2.0)Mean total volume of Alginate-hydrogel 4.6 (±0.6) mL

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AUGMENT-HF Study Design & Objectives

• Multicenter prospective randomized clinical trial• 78 Patients with moderate to severe HF that had been treated

with optimal medical and/or device therapy, randomized 1:1− 40 patients randomized to Algisyl implant procedure + optimal

standard medical therapy (SMT)− 38 patients randomized to optimal standard medical therapy alone

• 15 centers in Australia, Italy, Romania, Netherlands & Germany• Primary Efficacy Endpoint: peak VO2 assessed by a blinded core

lab • Secondary Endpoints: peak VO2, 6MWT, Symptoms, QOL and

measures of LV remodeling (echo) at 12, 18 and 24 months• Safety: clinical outcomes (MACE) adjudicated by blinded CEC

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• Inclusion criteria− Written informed consent− ischemic or non-ischemic HF patients who are symptomatic

despite optimal evidence-based therapies for HF − LVEF ≤ 35% − Peak VO2 of 9.0 - 14.5 mL/min/kg− LVEDDi 30 to 40mm/m2 (LVEDD/BSA)− Stable, evidence-based therapy for heart failure Previously reported high compliance: diuretics (99%) Beta Blockers

(95%), ARBs/ACE-enzyme inhibitors (89%) and MRAs (69%)• Exclusion criteria

− Acceptable renal, hepatic, stroke and MI status− LV wall thickness > 8 mm required for implant

AUGMENT-HF Key Inclusion & Exclusion Criteria

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AUGMENT-HF Baseline Demographics

Patients Completing 1-year follow-upAll Patients

(n=73)*All

(n=59)**Control(n=33)

Algisyl(n=26)

Age (years) 62.6 ± 9.6 63.2 ± 9.1 63.0 ± 9.3 63.5 ± 9.0

Ischemic HF 42 (58%) 35 (59%) 20 (61%) 15 (58%)

Non-ischemic HF 31 (42%) 24 (41%) 13 (39%) 11 (42%)

NYHA Class III/IV 81% 79% 76% 81%

LVEF (%) 25.5 ± 5.1 26.0 ± 5.0 25.9 ± 5.1 26.1 ± 5.0

Peak VO2 (mL/min/kg) 12.2 ± 1.8 12.4 ± 1.7 12.4 ± 1.7 12.3 ± 1.8

6MWT distance (m) 293 ± 84 292 ± 88 306 ± 81 275 ± 95

Mitral regurgitation ≥3+ 37 (51%) 27 (46%) 18 (55%) 9 (35%)

Hypertension 43 (59%) 37 (63%) 20 (61%) 17 (65%)

Diabetes 29 (40%) 25 (42%) 15 (46%) 10 (39%)

Previous PCI or CABG 20 (27%) 17 (29%) 9 (27%) 8 (31%)

* Modified Intention-to-Treat (mITT) population; ** 1 patient assessed by telephone only

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Peak VO2 - Mean Change from Baseline

Algisyl was superior to SMT at 12 months with a mean treatment effect of 2.10 mL/kg/min (CI 0.96–3.24). Algisyl patients completed the 1 year follow-up with a mean peak VO2 of 14.0 (±3.1) mL/min/kg

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Anaerobic Threshold – Mean Change from Baseline

AT is independent of patient motivation or effort. Algisyl was superior to SMT with a mean treatment effect of 2.34 mL/kg/min (CI 1.35–3.32) at 12 months (p<0.001).

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Six Minute Walk Test - Change from Baseline

Treatment effect (vs. SMT) of 101 meters for median 6MWT distance

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NYHA Functional Class at 12 months

At 12 months, 85% of patients in the Algisyl group were NYHA functional class I or II compared to 25% of patients on SMT. Only 4 patients in the Algisyl group remained in NYHA class III at 12 months. These differences were highly statistically significant. The odds ratio favoring improvement by one class for Algisyl was 31.90 (CI 7.6–133.4); P < 0.001

Odds Ratio: 31.90 (CI 7.6–133.4); P < 0.001

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OutcomesMean Difference

Algisyl vs. Standard Medical Therapy

P ValueAlgisyl vs. Standard

Medical Therapy

Peak VO2 (mL/kg/min) 2.10 < 0.001

Anaerobic Threshold (mL/kg/min) 2.34 < 0.001

Peak Watts 11.9 0.003

Total Exercise Time (min) 1.52 0.002

6-min walk test distance (m)a 101a < 0.001

NYHA class - 1.0 < 0.001

KCCQ Overall Summary score 13.4 0.016

KCCQ quality of life score 12.5 0.04a non-parametric test

AUGMENT-HF – Summary of 12 Month Outcomes

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Safety populationSMT

(N=38)Algisyl-LVR

(N=40)

Total #of events

# of patients with events

(%)

Total #of events

# of patients with events

(%)P

All adverse events 98 25 (66) 144 34 (85) <0.001#

Serious adverse events

44 18 (47) 50 21 (53) 0.186#

# p-value calculated by the log-rank test of the hazard ratio (hazard rate per 100 patient years at risk)

All Adverse Events at 12 months

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Safety population SMT(N=38)

Algisyl-LVR (N=40)

Event Total #of events

# of patients (%)

Total #of events

# of patients (%)

Death 4 4 (10.5%) 9 9 (22.5%)

Cardiovascular death 4 4 (10.5%) 8 8 (20.0%)

Non-cardiovascular death 0 0 (0.0%) 1 1 (2.5%)

MACE events (excluding index hospitalization) 38 15 (39.5%) 19 10 (25.0%)

Cardiovascular death 4 4 (10.5%) 6 6 (15.0%)

Cardiac arrest 3 3 (7.9%) 2 2 (5.0%)

Worsening heart failure 23 13 (34.2%) 11 6 (15.0%)

Sustained ventricular arrhythmias 8 5 (13.2%) 1 1 (2.5%)

MACE and Mortality – Blinded CEC Adjudication

The study was not powered to detect differences in event rates and there were no statistically significant differences between groups for any of these event categories

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AUGMENT-HF II – Large US PMA Study (recent FDA cleared IDE)

•Sample size of 240 patients, randomized 1:1 versus usual care

•Endpoints essentially identical to the prior AUGMENT-HF study

•Peak VO2 and Combined HF hospitalization and mortality

The Future of Algisyl

Algisyl as a Percutaneous Intervention

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• We previously reported that Algisyl injections can be administered safely in patients with advanced HF, with an acceptable 30 day post-operative morbidity & mortality.

• The one-year follow-up results from AUGMENT-HF trail demonstrate sustained long term benefits of the Algisyl implant procedure in patients with advanced HF

• Algisyl combined with SMT provided substantial improvements in functional capacity & HF symptoms when compared to patients on SMT alone at 1 year post treatment.

• The 1 year MACE suggest a potential favorable reduction in HF hospitalization in patients treated with Algisyl. However there was a trend towards higher CV mortality at 1 year for patients receiving Algisyl.

• Longer term observations for this patient cohort and larger studies will provide important insights into clinical outcomes such as HF hospitalization and CV mortality

Conclusions

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These results of the one year follow-up will be published online as an Epub ahead of print in the European Journal of Heart Failure following this presentation