Team advances research using growth factors to treat heart failure

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 - heart puzzle

A recently published study of heart failure from the University of California Los Angeles found that despite the availability of new devices and medications, the mortality rate for this condition continues to be very high, with 30 percent of patients dying within three years (Circulation: Heart Failure 2013; 6:411-419). The study also confirmed that patients with progressive heart failure are especially at risk even after trying implantable ventricular assist pumps or heart transplants, which can be challenging to tolerate.

In addition to these two treatments, there are several medications available for heart failure patients, such as angiotensin converting enzyme (ACE) inhibitors, angiotensin-II receptor blockers (ARBs), beta-blockers or loop diuretics. However, studies have shown that beta blockers and ARBs may have less than the desired beneficial effect (New Engl J Med online Nov. 11, 2008; J Am Coll Cardiol Heart Failure 2013; 1: 21-28). These treatments may help to improve symptoms or slow down the progression of the overall disease, but they do not address the underlying disease or improve the patient’s long-term prognosis.

Our research team at Vanderbilt University School of Medicine in Nashville, Tenn., has partnered with Acorda Therapeutics to evaluate the safety and efficacy of a new biological product that has the potential to treat patients with even severe, progressive heart failure. We are working with neuregulins, which are growth factors that work to repair the cardiac and nervous systems. Acorda has advanced a neuregulin known as GGF2 to clinical trials. GGF2 acts directly with cardiomyocytes to enhance the repair and function of cardiac muscle by promoting cell survival and maintaining myocardial homeostasis (J Mol Cell Cardiol 2011; 51[4]:501-504). GGF2 appears to make endogenous muscle stronger, which may prevent disease progression and the need for heart transplantation.

After preclinical studies showed that GGF2 could improve left ventricular heart function in animal models of MI, a Phase I clinical trial was initiated. The study included 40 patients who were previously optimized on standard therapies for heart failure. Results were presented at the 2013 American College of Cardiology Scientific Sessions in March. Findings indicated that GGF2 was able to improve ejection fraction (EF) compared to placebo in patients with heart failure after a single intravenous infusion. The average EF of study participants was approximately 28 percent at the start of the study and at day 28 the absolute mean change in EF was 12 percent for the cohort receiving the maximally tolerated dose of GGF2 (0.75mg) compared to 0 percent for the control group. Overall trends of long-lasting, dose-related improvement were observed in patients treated with GGF2.

In this study, a single dose of GGF2 in patients with heart failure was generally well tolerated up to 0.75 mg/kg. Among participants receiving GGF2, the most commonly observed adverse events were headache, site injection reaction and gastrointestinal symptoms. There were no notable effects of treatment on hematology or electrocardiogram, and no adverse events led to withdrawal from the study. A dose-limiting adverse event of hepatotoxicity meeting Hy’s Law criteria (elevated ALT, AST and bilirubin) occurred in the highest-dose cohort. The patient’s liver function tests and bilirubin had returned to normal by two weeks after dosing. There was also one reported case of uroepithelial carcinoma, a form of cancer in the cells that line the bladder, which was diagnosed three months after dosing in the highest-dose cohort. The patient’s baseline urinalysis showed the presence of red blood cells, indicating that the tumor was likely present prior to dosing.

Our team is very encouraged by the results of the Phase I study, which clearly supports continued research to assess the safety and long-term efficacy of treatment with GGF2. We are currently working with Acorda to continue development of GGF2 and a second clinical trial is expected to begin later in 2013. 

Dr.  Lenihan is director of the clinical research program and a professor of cardiovascular medicine at Vanderbilt University Medical Center.