A gene transfer therapy that delivers the adenylyl cyclase type 6 (AC6) protein via a modified adenovirus into the coronary artery showed early promise as a novel treatment for heart failure, according to a phase II trial.
In 56 patients, intracoronary delivery of adenovirus 5 encoding adenylyl cyclase 6 (Ad5.hAC6) was found to have a dose-related beneficial effect on cardiac function, including improvements in left ventricular function beyond standard therapy in a subset of patients with nonischemic heart failure monitored for up to 1 year versus placebo, wrote H. Kirk Hammond, MD, of the University of California San Diego and the VA San Diego Healthcare System, and colleagues.
AC6 gene transfer was not associated with increased adverse events, they wrote in JAMA Cardiology.
"Heart function improved considerably in at least a subset of patients, and at the highest dose we saw no increase in serious adverse events, " Hammond told MedPage Today. "There also appeared to be no ceiling on dose response."
The hospital admission rate among patients who received the AC6 gene transfer was just 9.5% (four of 42) during the trial, compared with 28.6% (four of 14) in the placebo group, but Hammond noted that the study was not powered to show this outcome (relative risk 0.33, 95% 0.08-1.36, P=0.10).
"This finding was encouraging, but for outcomes such as mortality and rehospitalization for heart failure, much larger studies will be needed," he said.
AC6 is a protein found in cardiac muscle cells which is key for regulating heart function. The protein appears to be down-regulated in heart failure patients, Hammond added.
The trial included heart failure patients treated at seven medical centers in the U.S. (one VA medical center, five academic centers, one community hospital) between mid-July 2010 and late October 2014. All patients had an ejection fraction (EF) of 40% or less when screened, and they were randomized to receive one of five doses of intracoronary Ad5.hAC6 or placebo.
In addition to baseline cardiac catheterization, the study participants underwent a second catheterization 4 weeks after treatment to measure left ventricular pressure development (+dP/dt) and decline (-dP/dt). Exercise testing and EF were assessed 4 and 12 weeks after randomization.
A total of 14 patients were randomized to receive placebo and 42 patients received a single administration of intracoronary Ad5.hAC5 at one of five ascending doses (3.2 x 109 to 1012 virus particles). Nitroprusside sodium was used to increase gene transfer efficiency.
Primary endpoints included exercise duration and EF before and at 4 and 12 weeks after randomization and peak rates of +dP/dt and -dP/dt before and 4 weeks after randomization. Mean EF at randomization was low (31%) among participants in all arms of the study.
Exercise duration showed no significant group differences at 4 weeks (P=0.27) and 12 weeks (P=0.47). AC6 gene transfer patients had increased EF at 4 weeks (+6.0 [1.7] EF units, n=21, P<0.004), but not 12 weeks (+3.0 [2.4] EF units, n=21, P=0.16). Placebo participants showed no increase in EF at 4 weeks or 12 weeks.
AC6 gene transfer increased LV peak -dP/dt (P<0.03) and AC6 gene transfer also increased EF in study participants with nonischemic heart failure (P=0.02).
Only nonischemic AC6 gene transfer patients showed a significant increase in EF at 12 weeks: EF fell by 0.8 (3.0) EF units in ischemic etiology patients, and increased by 8.2 (3.3) EF units in nonischemic patients. Repeat analysis confirmed this finding, the authors noted.
"Why would individuals with nonischemic heart failure have a superior response,?" the researchers wrote. "Perhaps reduced viable myocardium in those with ischemic heart failure impedes the response to AC6 gene transfer. Alternatively, because ischemia affects endothelial function, its presence may impede transvascular movement of the vector into the cardiac interstitium and thereby may curtail gene response."
The start-up biotechnology company Renova Therapeutics, which was founded by Hammond and colleagues, is in the planning phase of a larger study of the gene transfer therapy to confirm its safety and efficacy in patients with heart failure. The Renova-funded trial will likely include about 1,500 patients and will begin enrolling patients in about a year, he added.
This study was funded by the National Heart, Lung, and Blood Institute Gene Therapy Resource Program and Renova Therapeutics via an NIH Public Private Partnership.
The Belfer Gene Therapy Core Facility at Weill-Cornell manufactured Ad5.hAC6.
Hammond and some co-authors disclosed relevant relationships with Renova Therapeutics. One co-author disclosed relevant relationships with Topera, Abbott, Medtronic, Boston Scientific, St Jude Medical, and Biotronik.
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