Intracoronary Gene Transfer Improved Ejection Fraction in Heart Failure Interview with:

H Kirk Hammond, MD Professor of Medicine (Cardiology) University of California San Diego Veterans Affairs San Diego Healthcare System San Diego, CA 92161

Dr. H. Kirk Hammond

H Kirk Hammond, MD
Professor of Medicine (Cardiology)
University of California San Diego
Veterans Affairs San Diego Healthcare System
San Diego, CA 92161 What is the background for this study?

Dr. Hammond: Heart failure affects >28 million patients worldwide and is the only cardiovascular disease that is increasing in prevalence. Despite steady improvement in drug therapy for heart failure, recent hospitalization rates and mortality have changed little. New therapies are needed. Adenylyl cyclase type 6 (AC6), is a protein that catalyzes the conversion of ATP to cAMP and is an important determinant of heart function. The amount and function of AC6 are reduced in failing hearts, and preclinical studies have shown benefits of increased cardiac AC6 content on the heart. The aim of the trial was to determine safety and heart function gene transfer of AC6, achieved by intracoronary delivery of an inactivated virus carrying the gene for AC6 (Ad5hAC6) in patients with symptomatic heart failure and reduced ejection fraction. Our hypothesis was that AC6 gene transfer would safely increase function of the failing hearts of patients with heart failure. What are the main findings?

Dr. Hammond: In this randomized, double-blind, placebo-controlled clinical trial that included 56 participants with symptomatic heart failure and reduced ejection fraction, intracoronary delivery of Ad5.hAC6 (AC6 gene transfer) increased left ventricular function, and was safe:

• Annual heart failure hospital admission rate was 9.5% in patients that received AC6 and 28.6% in those who received placebo (P = 0.10).

• The rates of serious adverse events were similar in both groups.

•Two efficacy endpoints showed significant group differences:

  • o AC6 gene transfer increased LV peak −dP/dt (P <0.03), indicating improved LV diastolic function.
  • o AC6 gene transfer increased ejection fraction in participants with non-ischemic heart failure (P =0.02), indicating increased LV systolic function. What should clinicians and patients take away from your report?

Dr. Hammond: In patients with heart failure and reduced ejection fraction, AC6 gene transfer safely increased LV function beyond optimal heart failure therapy through a single administration. What recommendations do you have for future research as a result of this study?

Dr. Hammond: Larger trials are warranted, and are being planned, to assess the safety and efficacy of AC6 gene transfer for patients with heart failure. Is there anything else you would like to add?

Dr. Hammond: The preclinical and clinical study results are the culmination of years of collaborative work by the authors of the study and by scientists in Dr Hammond’s laboratory and other colleagues. This work was funded by National Institutes of Health (NIH) grants P01HL66941, National Heart, Lung, and Blood Institute (NHLBI) Gene Therapy Resource Program grant HHSN2682012000021, and Renova Therapeutics, Inc, via an NIH Public Private Partnership.

The funding organizations had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication. Dr Hammond is a founder, board member, and unpaid consultant to Renova Therapeutics, a start-up biotechnology company. Thank you for your contribution to the community.


Intracoronary Gene Transfer of Adenylyl Cyclase 6 in Patients With Heart Failure

Kirk Hammond MD, William F. Penny MD, Jay H. Traverse MD, Timothy D. Henry MD, Matthew W. Watkins MD, Clyde W. Yancy MD, Ranya N. Sweis MD, Eric D. Adler MD, Amit N. Patel MD, David R. Murray MD, Robert S. Ross MD, Valmik Bhargava PhD, Alan Maisel MD, Denise D. Barnard MD, N. Chin Lai PhD, Nancy D. Dalton RDCS, Martin L. Lee PhD, Sanjiv M. Narayan MD, Daniel G. Blanchard MD, Mei Hua Gao PhD
JAMA Cardiol. doi:10.1001/jamacardio.2016.0008 Published online March 30, 2016.

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Dr. H Kirk Hammond (2016). Intracoronary Gene Transfer Improved Ejection Fraction in Heart Failure