Armand Guiguemde, PhD (at right), discusses the hospital’s malaria research efforts with Kip Guy, PhD, Chemical Biology and Therapeutics chair.

St. Jude Tells Malaria to BUZZ OFF

By Maureen Salamon
Photography by Peter Barta and Ann-Margaret Hedges

Spread by mosquitoes, malaria is a worldwide killer of children. St. Jude scientists and clinicians have teamed up to create a potential new malaria drug that could save untold lives.

Armand Guiguemde, PhD, remembers only the blistering fever and throbbing headache.

As a 9-year-old boy in the West African country of Burkina Faso, Guiguemde had no idea his intense symptoms signaled one of the world’s leading killers of children: malaria. Fortunately, his grandfather had the insight to seek prompt medical care for Guiguemde, sparing him from a coma or even death.

More than three decades later, Guiguemde’s experience has come full circle with his participation in an effort by St. Jude Children’s Research Hospital to attack malaria, which claimed about 438,000 people globally in 2015.

Caused by Plasmodium parasites spread through the bites of infected Anopheles mosquitoes, the scourge has outwitted existing medications. Children under age 5, whose immune systems are especially vulnerable, constitute more than 70 percent of malaria-related deaths worldwide.

St. Jude scientists have headed an international collaboration to develop a fast-acting, single-dose malaria drug they expect to be a game-changer on a global scale. Although hospital staff have led similar projects for vaccines and gene therapy initiatives, this is the first “soup-to-nuts” small-molecule project at St. Jude—in which a novel compound is created in the lab and brought to clinical trials.

“Many kids my age died of malaria when I was a child, and it’s great to know that now we may be able to prevent that from happening for the next generation,” says Guiguemde, now 42, and a malaria researcher in St. Jude Chemical Biology and Therapeutics. “Malaria’s still a big killer. So whatever we can do to save lives is going to be a dream come true for me.”

Fast-acting compound 

Kip Guy, PhD, barely dared to dream a decade ago that his long effort to discover a new malaria drug could pay off with such a stunning prospect. Chair of St. Jude Chemical Biology and Therapeutics, Guy leads a team focused on discovering new drug leads that work against the molecular targets that fuel disease.

Malaria control has been increasingly difficult because of emerging drug resistance. But by 2010, St. Jude researchers and their international colleagues had found new starting points for drug discovery. Scientists tested the effectiveness of more than 300,000 chemicals against the malarial parasite. The team identified nearly two dozen families of molecules as possible drug-development candidates.

With these starting points in hand, Guy organized a consortium of laboratories, including key collaborators at Rutgers University; the University of California, San Francisco; and the University of South Florida. Within two years, the team had identified a winning compound: Known as (+)-SJ733, the agent tricks the immune system into rapidly destroying red blood cells infected with the malaria parasite but leaves healthy cells unharmed.

Even more compelling is the compound’s speed. It killed 80 percent of malaria parasites within 24 hours. No parasites were detectable after 48 hours.

“We were quite surprised at how rapidly it acted in vivo,” Guy says. “In fact, that really energized the whole project team to push much harder on the compound. It moved from a project of interest to something we thought was at the front edge of all the available malaria drug candidates in the world. I think that’s actually proven to be the case.”

“For most medicinal chemists, you’re lucky if this kind of breakthrough happens once in your career,” he adds. “I’m 25 years into doing this, and it’s the first time for me.”

Avoiding drug resistance

Malaria remains among the top threats to children in the developing world. In fact, according to the World Health Organization, the disease kills one child in Africa every minute. Yet, financial investments in malaria research petered out in the mid-20th century, after the disease was eradicated in Europe and the U.S. Interest rebounded in the last 15 years, as the malaria parasite began to outsmart the mainstay drugs that had beaten back death rates.

Existing frontline drugs seem to be losing effectiveness among malaria patients in Asia. Guy says this could set up a terrifying scenario in which drug resistance spreads throughout the developing world.

“We roughly halved the number of children dying each year, due to the introduction of those drugs in Africa,” he explains. “If we lose that backbone therapy, we could go back up to 1 million or 1.5 million children dying every year. It’s a horrifying prospect.”

That’s why it’s especially valuable that (+)-SJ733 is part of an entirely different class from existing drugs.

The new compound should skirt the drug resistance chipping away at other medications’ power. The potency of (+)-SJ733 is driven by host responses to the treated, infected red blood cells. The agent also works in both the blood and sexual stages of the disease, extending its punch beyond treatment to blocking transmission between patients.

“I would put it in a very unusual category with a small number of other anti-malarials,” Guy says. “This is a property we’ve all been looking for.” 

 
Joshua Wolf, MD, and Aditya Gaur, MD

BUZZOFF principal investigator Aditya Gaur, MD, (at right) discusses nuances of the clinical trial with the study’s first healthy volunteer, Joshua Wolf, MD, of St. Jude Infectious Diseases. “As a clinical researcher, I jumped at the opportunity to put my money where my mouth is,” says Wolf, who usually has the role of recruiter instead of research participant.

Testing the compound

Now underway is the first phase of a clinical trial that may make (+)-SJ733 an exciting new prospect in the malaria clinical realm.

Dubbed the BUZZOFF Trial­—a catchy nod to enemy mosquitoes—the study’s kickoff phase is based in Memphis and involves 30 healthy adults. Clinicians are examining the safety and potential side effects of escalating doses of (+)-SJ733 among these volunteers. This phase, which should continue through the summer, will also measure blood levels of the drug. The goal is to establish which dose consistently leads to a therapeutic level.

On the heels of this data will be the trial’s next phase, which will be based in Australia. This part of the study will test (+)-SJ733 in groups of eight to 12 people.

After being infected with a strain of malaria known to respond to standard treatment, the volunteers in Australia will be carefully observed while their blood is tested every 12 hours for malaria activity. Once such activity is detected, they’ll be given the therapeutic dose of (+)-SJ733 that was established in the trial’s first phase. With blood tests continuing, the volunteers will receive standard anti-malarial drugs a few days later regardless of whether they ever develop symptoms of the disease.

 “We’re among the few pediatric-focused research facilities that have the scientific expertise in the basic science area to be able to have such drug discovery and then the resources on campus to take it through early-stage drug development,” says BUZZOFF principal investigator Aditya Gaur, MD, of St. Jude Infectious Diseases.

“We also have the clinical research infrastructure to be able to design and execute the first human trial,” he adds. “It’s something unique to a very small group of academic institutions.”

Gaur points out that dozens of employees in a wide variety of departments and organizations worked in tandem to design and oversee the thousands of details required to launch the clinical trial. 

“The phrase, ‘It takes a village,’ is so applicable to this experience,” he says. “The unsung heroes of everyday clinical research are the ones who make these studies possible.”

Worldwide impact

Gaur anticipates that a few more years will pass before the breakthrough malaria pill (+)-SJ733 gains U.S. Food and Drug Administration approval and is ready for the market. But he, Guiguemde and Guy are keeping their eyes on the prize, eagerly anticipating the compound’s contribution to malaria control.

While it may be a cure in itself, it’s more likely to be an important part of a combination of drugs, says Gaur, who, until 1996, worked as a pediatrician in India, where malaria is common.

“I think the expectation would be that a single dose does 80 or 90 percent of the job, and then combined with another medication, provides a successful treatment of malaria that’s starting to become resistant to current drugs,” Gaur says.

Guy has high hopes for the eventual impact of (+)-SJ733.

 “I think if we put this drug in the clinic and it works, it’s going to positively affect the lives of a lot of children,” he says. “That’s exactly the kind of legacy that our hospital’s founder, Danny Thomas, wanted.”

From Promise, Spring 2016

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