The Accidental Drug Developer
Steady research trek leads from the bench to the bedside of patients with failing hearts
Doug Sawyer wasn’t looking for a new treatment for heart failure when he started his research fellowship 15 years ago. As a cardiologist, he was interested in helping patients with the condition, to be sure, but as a scientist, he was more intrigued by the biology of heart muscle cells. He wanted to understand how these cells maintain themselves for a lifetime.
“How do constantly beating cardiac myocytes (muscle cells) withstand the wear-and-tear of contraction? And how do they survive for so many years?” wonders Sawyer, M.D., Ph.D., Lisa M. Jacobson Professor of Medicine and chief of the Division of Cardiovascular Medicine at Vanderbilt University Medical Center.
Sawyer and other investigators have zeroed in on a survival factor – a protein called Glial Growth Factor 2 (GGF2) – that protects cardiac myocytes from stressors in culture and enhances heart function and survival in animal models of heart failure. Now, Sawyer and colleagues at Acorda Therapeutics are poised to test GGF2 for the first time in human patients.
If the first trials show that GGF2 is safe and well tolerated by patients, the investigators will pursue further clinical trials.
GGF2 represents a potentially new approach for treating heart failure, a chronic condition in which the heart is unable to meet the body’s demands, leaving patients short of breath and unable to complete daily activities. Current medications address the symptoms of fluid build-up and aim to modify the heart’s workload, but GGF2 appears to enhance the repair of damaged heart muscle.
“I never expected to be so fortunate as to be involved with something that’s gone all the way from studies at the bench to the point where we’re going to give it to people to see if it might help them,” Sawyer says. “I feel very lucky in that regard.”
Probing cardiac cell survival
As its name suggests, Glial Growth Factor 2 was first characterized for its growth-promoting actions on glia, cells that support and protect neurons in the nervous system. GGF2 is a member of a family of proteins called neuregulins, which themselves are part of an even larger family of epidermal growth factor (EGF) proteins. Vanderbilt’s Stanley Cohen, Ph.D., was awarded the Nobel Prize in 1986 for his discovery of EGF.
GGF2 landed in Sawyer’s hands by chance.
He was new to the research group of Ralph Kelly, M.D., and Thomas W. Smith, M.D., experts on cardiac myocyte biology, at Brigham and Women’s Hospital, where he had begun to study the effects of cancer drugs called anthracyclines (such as adriamycin) on cultured cardiac myocytes. These drugs were known to cause heart failure in cancer patients, and Sawyer was testing whether they killed heart cells the same way they killed cancer cells. He was also examining factors that might improve cell survival.
Mark Marchionni, Ph.D., at a company called Cambridge Neurosciences, had approached Kelly about looking at the effects of GGF2 on cardiac myocytes. Marchionni had cloned the gene for GGF2 and coined the term “neuregulin.”
“The GGF2 project was an orphan in the lab, and Ralph Kelly said to me, ‘why don’t you study GGF2 in the myocytes while you’re doing your other experiments,’” Sawyer recalls.
He included GGF2 in a panel of factors he was testing, and he found that GGF2 regulated myocyte survival – with GGF2 around, the cells lived longer, even after stressors like anthracyclines.
“That result made GGF2 much more interesting to me,” Sawyer chuckles.
GGF2 had been studied in other cell types and was known to work through the EGF family of erbB receptors. Sawyer used those previous reports as a starting point for his own examination of the receptors and signaling pathways activated by GGF2 in cardiac myocytes.
Findings were also emerging from other groups that neuregulins played critical roles in the developing heart. Mice missing neuregulin-1 (GGF2 is a version of this neuregulin) or its receptors erbB2 or erbB4 died in utero because of failures in heart development.
Sawyer and Kelly speculated that if GGF2 improved cell survival in the setting of heart failure, it might be a good therapy for the condition. So Cambridge Neurosciences patented GGF2 and other neuregulins as potential treatments for heart failure. Sawyer is an inventor on the patent, but he didn’t intend to continue his neuregulin research. Instead, after finishing his fellowship, he took a faculty position at Boston University and continued his studies of anthracycline toxicity, oxidant stress, and cardiac cell survival.
“I just went about my business,” he says. “I didn’t know what was going to happen with the neuregulins, but I figured I was better off pursuing my interest in cardiac myocyte biology and leaving the drug development to the company.”
Then chance intervened again. A new cancer drug – Herceptin – was introduced, and it caused heart failure in patients with breast cancer, particularly those who were also taking anthracyclines.
Clues from the clinic
Herceptin was developed to block erbB2 receptors, which are activated by epidermal growth factor family members, including neuregulins. Breast cancers with increased levels of erbB2 receptors – also called HER2/neu receptors – are more aggressive and have a worse prognosis compared to breast cancers that do not overexpress erbB2.
“Herceptin’s cardiac effects demonstrated in humans that this neuregulin signaling system matters in the heart – if you interrupt it, it’s bad news,” Sawyer says.
Genentech, the manufacturer of Herceptin, invited Sawyer and others to submit grants to study the roles of neuregulins, anthracyclines and Herceptin in cardiac biology. Sawyer was awarded a Genentech grant.
“I basically dove back into neuregulin biology,” Sawyer says. “And we stayed focused on the biology, rather than the therapeutic development.”
Sawyer’s team learned which heart cells express neuregulins, and which neuregulin form is most potent in regulating cell survival. They discovered how neuregulins modulate cell metabolism and cell growth. And they explored how the body controls neuregulin expression and activity – and how that might go awry in heart failure.
Other groups found that erbB receptor expression drops in animal models of heart failure and in human tissues from patients with heart failure, further implicating the signaling system in the condition.
During this time, Acorda Therapeutics, a neurosciences-focused company, bought the neuregulin technologies from Cambridge Neurosciences/ Cenes and pursued development of GGF2 for a range of neurologic and cardiac conditions, including stroke and heart failure.
In 2006, data supporting the therapeutic potential of neuregulins in heart failure “reached a tipping point,” Sawyer says.
Researchers at Zensun, a company in China, reported that a version of neuregulin-1 (different from GGF2) improved cardiac function and survival in animal models of heart failure caused by ischemic injury (like a heart attack), cancer drugs and viruses.
“I was happy – and surprised – to see those results,” Sawyer says. “I honestly never believed neuregulin was going to go anywhere therapeutically because in cancer it could promote growth.”
Therapeutic development was never his mission, he says, rather, he was interested in maintaining a grant-funded basic science lab and in training new investigators to study cardiac myocyte biology.
But another chance occurrence – a new grant mechanism – brought Sawyer into the drug development arena.
Back to the bedside
Just after the Zensun findings were reported, the National Heart, Lung and Blood Institute introduced the Cardiac Translational Research Implementation Program (C-TRIP) to advance research on promising new therapeutics for heart failure and arrhythmias.
Vanderbilt and Acorda received a C-TRIP grant in 2010, which is supporting additional studies of GGF2 in animal models of heart failure and a Phase I clinical trial to assess the safety of GGF2 in human patients with heart failure. Acorda is sponsoring another Phase I trial of GGF2 at Vanderbilt.
“C-TRIP has been a great mechanism for pulling academic and industrial groups together,” says Anthony Caggiano, M.D., Ph.D., vice president of Preclinical Development at Acorda and a co-principal investigator with Sawyer on the C-TRIP grant.
“Our collaboration over the years, and now with this grant, has been ideal in that our strengths are complementary and only somewhat overlapping. Acorda has strength in drug development science, while Dr. Sawyer and his colleagues have basic science and cardiology expertise.”
The Phase I trials of GGF2, being led by Daniel Lenihan, M.D., professor of Medicine, and Carrie Geisberg, M.D., assistant professor of Medicine, are designed to study GGF2 safety and dosing. The investigators also will be looking at measures of heart function – using blood biomarkers and non-invasive imaging including echocardiography – to gather information that would support further clinical testing.
“We’re really excited about these trials,” Lenihan says. “We have a lot of room for improvement in treating heart failure,” which he notes is the most common reason for hospital admission in the United States.
“We think that GGF2 is going to enhance the repair of damaged heart muscle, no matter what has caused the damage,” Lenihan says. “That’s really a whole line of therapy for heart failure that we haven’t investigated. There are no therapies that do that right now.”
“I think it’s a good experiment. It’s worthwhile to test GGF2 in people,” Sawyer says. “We know that the chances of success for any experimental therapeutic are small, but we’re hopeful that GGF2 will help patients with heart failure.”
Chance, after all, seems to be on Sawyer’s side.