Chemical Renal Denervation Update and Future Directions Tim A. Fischell, M.D., FACC, FSCAI Professor of Medicine Michigan State University

Tim A. Fischell, M.D. Ablative Solutions, Inc. Abbott Vascular   I have the following financial disclosures: Ablative Solutions, Inc. Founder, Co-Inventor Officer and Stockholder   Abbott Vascular Member, Medical Advisory Board

Important Disclosures About the Peregrine System™ Kit THE PEREGRINE SYSTEM KIT IS: An investigational product not currently approved in the United States Limited to investigational use in clinical trials Currently being studied as a combination drug/device product to evaluate safety and effectiveness for renal denervation in the TARGET BP I Trial under an investigational new drug (IND) application This presentation reports clinical data collected with the use of the CE Mark Peregrine System™ Infusion with a neurolytic agent (dehydrated alcohol) for the treatment of patients with systemic hypertension This presentation is intended solely to aid in scientific discussion and exchange surrounding the development and further evaluation of the product for this use

Post-Symplicity HTN-3 Analysis Suggests Design Flaws and “Inadequate Denervation”* Findings from Report Renal denervation will work only if sufficient ablation is provided 50% of patients did not receive the minimum of eight total ablations Adequate treatments (9-10 ablations/artery) with RF requires a vessel length of at least 4-5 cm The majority of patients don’t have vessels this long * Cardiology News: Renal denervation Proceeds as U.S. Trial’s Flaws Emerge, June 23, 2014; Kandzari et al, Eur Heart J, 2015

Alcohol-Mediated Denervation via Precise Nerve Targeting Device Perivascular Sites Where Device Infuses Alcohol Expanded View of Device Infusing Alcohol Site-specific delivery of alcohol targeted for local nerve inactivation Micro-volume (0.3 mL−0.6 mL) infused directly to the perivascular region Extracellular fluid helps spread alcohol circumferentially in the perivascular region Alcohol activity range self-limited through dilution by extracellular fluid CAUTION: The Peregrine System kit is currently being studied to evaluate safety and efficacy for renal denervation. It is an investigational product not approved in the US. Its use is limited to investigational use in clinical trials. The Peregrine System™ Infusion Catheter is CE Marked, and only for use in the European Union

Alcohol-Mediated Neurolysis: Animation CAUTION: The Peregrine System kit is currently being studied to evaluate safety and efficacy for renal denervation. It is an investigational product not approved in the US. Its use is limited to investigational use in clinical trials. The Peregrine System™ Infusion Catheter is CE Marked, and only for use in the European Union

Patient Treatment via Peregrine in Post-Market Study CAUTION: The Peregrine System™ Infusion Catheter is CE Marked, and only for use in the European Union

Dose Response/Efficacy Based on Four Independent Surrogate Markers* % quadrants with injury: score of 3 or 4 (0 to 4 scale) Norepinephrine: % reduction relative to controls TH decrease: Maximum reduction = 4 Nerve injury score: 0 to 4 scale *Fischell, et al.; Cardiovascular Revascularization Medicine, 16, 221-227 (2015) Quadrants with significant nerve injury(%) (%) Norepinephrine Reduction / Initial dose Current dose Alcohol-mediated dose response observed with multiple, independent bio-markers in animal studies

Global Clinical Road Map Summary: Stepwise Approaches to Evaluate Technology Safety/Performance N = 10 pts Study Closed for Enrollment CE Mark 5/1/15 First-Human-Use Study (Paraguay) N = 18 Study Complete RCT double-blinded 2:1 (RDN vs. no RDN) 100 pts Primary endpoint: mean 24-hour ABPM at 8 weeks Post-Market Study Single arm, open label, 0.6 mL alcohol/artery N = up to 120* Peregrine System™ Kit (Peregrine catheter + Alcohol) Peregrine System™ Infusion Catheter (Peregrine catheter + Neurolytic agent e.g. alcohol) Global Europe Enrollment Underway IND Allowed to Proceed * As per Notified Body guidance CAUTION: The Peregrine System kit is currently being studied to evaluate safety and efficacy for renal denervation. It is an investigational product not approved in the US. Its use is limited to investigational use in clinical trials. The Peregrine System™ Infusion Catheter is CE Marked, and only for use in the European Union

Clinical Trials: FIM and Pre-CE (N = 28 subjects; 38 procedures; 57 renal arteries) Peregrine System™ Infusion Catheter successfully navigated to target site in all renal arteries, including complex anatomy (short, tortuous segments, etc.) Device performance appears to be successful during all 38 procedures with 97.3% device success (1 device failure prior to start of procedure in the FIM) All vessels (57 in 28 subjects) treated as intended Minimal to no sedation during the procedures, with short treatment time: average time/renal artery = 9 ± 5 min Minimal contrast (average 67 ± 25 mL/procedure) and radiation exposure (average 10 ± 12 min/procedure). FIM: Systolic Office BP Drop: mean -25 mmHg at 1-M, and mean -22 mmHg at 6-M Peregrine Study (pre-CE): Systolic Office BP Drop: mean -29 mmHg and -37 mmHg at 1-M and 3-M (n=10). 24-Hour systolic ABPM drop: mean -12 mmHg and -7 mmHg at 1-M and 3-M, and was maintained at 12-M (-7 mmHg) (n=10) CAUTION: The Peregrine System™ Infusion Catheter is CE Marked, and only for use in the European Union. TCT2016 and on file at ASI.

Angiographic Follow-Up -> No Stenosis Angiographic Follow-Up -> No Stenosis* (n = 57 arteries in 28 Subjects) Baseline Baseline Baseline Baseline 6 Months 6 Months 6 Months 6 Months CAUTION: The Peregrine System™ Infusion Catheter is CE Marked, and only for use in the European Union. *As adjudicated by independent core lab

The “Peregrine Post-Market” Study (Europe) (Enrollment & Treatment Stage) A Post-Market Study of Transcatheter Perivascular Renal Denervation for the Treatment of Hypertension using the Ablative Solutions Inc. Peregrine System™ Infusion Catheter Study Designed to Satisfy Requirement of Notified Body Horst Sievert, MD Int. Cardiologist Peter Blankestijn, MD Nephrologist Atul Pathak, MD Hypertensionist Felix Mahfoud, MD Co-Lead Investigators and Steering Committee Members CAUTION: The Peregrine System™ Infusion Catheter is CE Marked, and only for use in the European Union

The “Target BP I” Study (Global) A Multicenter, Double-Blind, Sham-Procedure-Controlled Trial of Renal Denervation with Alcohol as delivered by the Peregrine System Infusion Catheter in Hypertensive Subjects US: IND allowed by FDA to be initiated in the US – EU: Submission on hold Global Steering Committee David Kandzari, MD Int. Cardiologist Michael Weber, MD Hypertensionist Maurice Buchbinder, MD Melvin Lobo, MD Mathew Weir, MD Nephrologist Atul Pathak, MD Ronald Schmieder, MD Felix Mahfoud, MD Co-Principal Investigators (US) Co-Principal Investigators (Europe) CAUTION: The Peregrine System kit is currently being studied to evaluate safety and efficacy for renal denervation. It is an investigational product not approved in the US. Its use is limited to investigational use in clinical trials.

Summary/Conclusions Preclinical studies suggest that chemical renal denervation using alcohol, with the Peregrine System Infusion Catheter appears to provide substantial sympathetic denervation, with favorable safety profile. Early clinical studies (FIM and the Peregrine (pre-CE study)) suggested consistent safety and performance of the Peregrine Catheter. Anatomical safety at 6-month imaging by Angio and CTA with no apparent evidence of tear, dissection, or new restenosis in any of the 57 renal arteries treated, as confirmed by independent core labs Early data from these clinical studies suggest a signal of efficacy with drop in blood pressure at various stages of the follow-ups. Larger controlled randomized blinded studies are needed to validate efficacy. Patient enrollment continues in the Peregrine Post-Market Study in EU with treatment at the “new” volume of 0.6 mL/artery, with efficacy and safety data being collected. “Target BP I”: FDA allowed initiation of study under its IND in the US and the company expects to start enrollment in 2017. CAUTION: The Peregrine System kit is currently being studied to evaluate safety and efficacy for renal denervation. It is an investigational product not approved in the US. Its use is limited to investigational use in clinical trials. The Peregrine System™ Infusion Catheter is CE Marked, and only for use in the European Union