By Liam O'Neil, Heart Failure 2015, Seveille, Spain

Principal investigator, Dr Penn, stated that based on the literature the degree of heart remodelling induced by SDF-1 over-expression should give a greater than 80% chance of mortality benefit in future trials.

Dr Penn said: “Molecularly, it makes sense to treat chronic heart failure patients with SDF-1 over-expression. Our body naturally expresses SDF-1 after injury but it doesn’t do so for long enough. At least 14 days of expression is needed to drive the recruitment of enough stem cells to start inducing tissue repair.”

Dr Penn previously showed that plasmid stromal cell-derived factor-1 (SDF-1) recruits the body’s own stem cells at sites of injured tissue. In a phase I study SDF-1 improved symptoms in heart failure patients. SDF-1 recruits bone marrow derived stem cells to the site of tissue injury to grow new blood vessels; recruits cardiac stem cells to possibly regenerate and improve heart function; blocks cell death; and remodels scar.

STOP-HF was a phase II, double blind, randomised, placebo controlled trial that evaluated the safety and efficacy of SDF-1 in patients with ischaemic heart failure. The study included 93 patients with ischaemic heart failure who had a left ventricular ejection fraction (LVEF) of 40% or lower and were symptomatic, as indicated by a Minnesota Living with Heart Failure Questionnaire score of 20 points or more (higher being worse) and a 6 minute walk distance of 400 metres or less. Patients were randomised 1:1:1 to receive a single treatment of 15mg or 30mg SDF-1 or placebo and were followed for 12 months. SDF-1 was delivered to the heart as 15 injections using an endocardial injection catheter inserted through the groin. The location of injections was determined by echocardiogram.

The primary endpoint of the trial was a composite score of 6 minute walk distance and quality of life questionnaire. The composite endpoint was significantly increased in both the control and treated cohorts.  As a result the trial did not achieve statistical significance on the primary endpoint.

In the entire population, patients treated with SDF-1 trended to an improvement in LVEF and LV end systolic volume (LVESV) although the results were not significant. In a prespecified analysis of the effect of the drug based on heart function at trial entry, patients with the worst heart failure (LVEF less than 26%) given 30 mg SDF-1 had a 7% increase in LVEF compared to a 4% decrease in the placebo group (p<0.01) at 12 months. They also trended towards a 18.5 ml decrease in LVESV compared to a 15 ml increase with placebo (p=0.10). There were no serious adverse events due to the drug JVS-100 in this trial.

Dr Penn said: “We found that high risk patients, particularly those patients with weaker hearts, had more significant remodelling of their hearts with improvement in the squeeze (ejection fraction) and decrease in the size of the heart. These improvements in LVEF and LVESV are 80% likely to result in a 2 year reduction in mortality of 20%, based on probability estimates developed from multiple clinical trials.”

Based on the analysis of this subpopulation, Dr Penn noted that it was possible that the study would have reached statistical significance if enrolment had been limited to high risk patients given the 30 mg dose of SDF-1. “The phase II STOP-HF 2 trial is under review by the FDA,” he said. “It will focus on high risk heart failure patients who will receive a 30 mg dose of SDF-1, followed by a second 30 mg dose 6 months later.”

He concluded: “We think in the future SDF-1 may be used in the prevention of heart failure as well as the treatment of existing heart failure. We need to understand exactly where the peak clinical benefit of SDF-1 will be. Based on animal studies it may be that we can prevent less sick heart failure patients from progressing to class III. The prototypical trial for this effect was the SOLVD Prevention Trial which showed that ACE inhibitors prevent progression to heart failure.”