UK Dean Part of Team that Discovers Promising Anti-Malarial Drug

It’s not unusual for research projects to take years, even decades, to complete. The work that goes into them is often developed over the lifetime of careers. For the last 15 years, Kip Guy, dean of the University of Kentucky’s College of Pharmacy, has been working on a project that is close to his heart.

“I’ve made it my life’s mission to help populations of people who are economically and logistically underserved for health care,” Guy said. “Whether that’s here in Kentucky, or across the world in Africa, I focus a lot of my work on organizing scientific programs that think beyond the drug.”

His drive to think outside the box has led him and a team of researchers to discover a potentially life-changing drug for a heavily drug-resistant disease.

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According to the World Health Organization (WHO) every two minutes a child dies of malaria and each year, more than 200 million new cases of the disease are reported. It’s the single largest cause of death in children worldwide.

“We’re interested in finding a new way to attack the disease that didn’t exist before and proving that works,” Guy said.

Malaria is caused by a parasite that is transmitted by infected mosquitos. Children are the most vulnerable to the disease, which destroys red blood cells. Artemisinin-based combination drug therapy, ACT, is used as a first-line treatment for malaria. WHO recommends using ACT because it combines two active ingredients with different mechanisms of action. Currently, it’s the most effective antimalarial medicine available, but drug resistance is on the rise. Guy noted that in central Asia, up to 60% of patients have a drug-resistant form of malaria.

“You need different drugs to treat different patient populations and we have a very small number of available drugs for malaria,” Guy said. “The majority of the ones we have been around for 20, 40, sometimes 50 years. In fact, until very recently, the last registry was the mid-70’s.”

Another issue, Guy says, is how our view of safety has changed over the years. What drugs we once favored are outdated and they’re failing to keep up.

The solution – SJ733

A team of researchers organized by Guy, including those at the University of Kentucky, St. Jude Children’s Research Hospital in Tennessee, Eisai in both the United States and Japan, Medicines for Malaria Venture (MMV) in Switzerland and QIMR in Australia, discovered a new, fast-acting anti-malarial compound that has shown promise in fighting malaria. The compound, SJ733, is one of the first in a new class of anti-malarial compounds to reach clinical trials, which are now in Phase II. So far, about 50 humans have been a part of the testing.

The compound works by disrupting the malaria parasite’s ability to remove excess sodium from red blood cells. As sodium builds up, infected cells become less flexible. The cells are removed by the immune system or get caught in small blood vessels.

The process

Guy started this research during his tenure as a professor at the University of California San Francisco.

“At that point, it was technology-oriented,” he said. “We partnered with Joe DeRisi, who now runs the Chan Zuckerberg Institute, and developed a way to search for compounds that acted on the parasite in a host cell.”

Several years later, Guy was recruited to St. Jude Children’s Research Hospital to serve as the chair of the St. Jude Department of Chemical Biology and Therapeutics. He continued to develop this methodology and was able to adapt a robotic system that let his team test millions of potential compounds.

A few years later, the team expanded to include MMV, Eisai and QIMR and moved into Phase I of clinical trials to test safety. The Eisai group, led by Fabian Gusovsky, coordinated the toxicology and drug produce manufacture.

The first phase was split into two studies – a total of 38 healthy volunteers were recruited as part of the Phase 1a study in Memphis, led by Aditya Gaur of St. Jude, and Phase 1b study in Brisbane, Australia, led by James McCarthy at QIMR. Twenty-three of the volunteers in Memphis received increasing doses of SJ733. The testing helps researchers to understand the dosing, safety profile and metabolism, including absorption.

Based on those results, 15 Australian volunteers underwent modified testing. These volunteers received SJ733 after being infected with malaria in the clinic. This allowed researchers to understand the anti-malarial effectiveness of the new drug by looking at the level of parasites in their blood and treating accordingly. The participants also received a curative dose of conventional anti-malarial combination therapy.

“To date, this has been a really safe drug. We’ve had no serious adverse events, and nobody has stopped taking it while they were on it, which is encouraging,” Guy said.

Also encouraging is how rapidly the drug acts. It’s significant, Guy said, because if someone is very sick, the drug has shown that it can make you feel better within a day or two. “We’re reducing the likelihood that a patient would die,” said Guy.

The next step

After moving to Kentucky in 2016 to further his career in higher education as a professor and the dean of the UK College of Pharmacy, Guy continued his research with a team at UK.

Now, SJ733 is Phase II, which is taking place in Peru. To do that, the team has added Clinica Selva Amazonica, under the leadership of Alejandro Llanos-Cuentas. Patients in the clinic often present with both types of major malaria – something that helps to test the drug against both strains.  

After almost 20 years of research and development, Guy hopes to register this drug in the United States. While it’s a process that will likely take another six to seven years, he’s hopeful for what’s to come.

“Twenty years, in this business, is pretty normal,” he said. “Most people who do what I do for a living are doing well to get one compound in the clinic. This feels really good.”

Guy appreciates the wide variety of research that goes on at UK beyond his college – the work being done across disciplines, institution-wide. He’s inspired by UK’s orientation to impact.

“It’s a very collaborative and interactive place,” he said. “It’s that collaboration that has, in many ways, contributed to our success.”