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Researcher Meets Challenges in Developing Drug

September 10, 2002

Heather Heilman

The man or woman on the street in New Orleans is convinced that malaria has been eradicated," said Don Krogstad. "Their interest in volunteering for a malaria study is about as close to zero as you can get."

That apathy was just one of many challenges Krogstad faced in the development of a new anti-malarial drug. Malaria has been eradicated in the United States, but across the globe more than a million people die of it every year, most of them African children.

Chloroquine has historically been an effective treatment for malaria, but increasingly drug-resistant strains of the disease have developed and spread. Krogstad, chair of tropical medicine, became interested in malaria while working for the Peace Corps in Haiti and East Africa. Back in the United States, his research focused on malaria and the drugs used to treat it.

He came to Tulane in 1992 with a basic science grant and the goal of making some analogs of chloroquine in order to figure out which part of the molecule makes it effective against malaria and which part is resisted. In the lab, he found that 40 percent of the analogs he'd made were active against some of the parasites that cause malaria, and 20 percent were active against all known drug-resistant parasites.

"That was, to put in mildly, a shock," said Krogstad. When drug companies try out new compounds, finding one in a thousand that is biologically active is considered a very good result. "Hit rates of 20 and 40 percent are off the scale," Krogstad said. "I didn't believe the numbers. We kept going back and doing it again until I was finally beaten into surrender. Then the question was, what do I do now?"

Krogstad approached the Tulane Regional Primate Center about testing the compounds in monkeys. Two monkey models were developed, one with a type of malaria similar to that prevalent in Africa, and another like that seen in Asia and South America. Two new compounds were tested and both eliminated the parasite. The compounds were equally as effective in treating the drug-resistant form of the disease. Krogstad brought the results to the attention of the Food and Drug Administration in 1996.

"They were encouraging in an intellectual sense, but they told us we wouldn't be able to test anything in people until we had done the kind of animal studies necessary to get an investigational new drug (IND) patent."

Within two years he had received his IND and was ready to begin phase one studies comparing one of the new compounds, now dubbed AQ-13, to chloroquine. Funding was a bit of a problem. "It can be tricky to write the grants and juggle the availability of funds so that you don't ever run dry and you don't have too much money early when you can't use it and no money later when you still need it," Krogstad said.

The Tulane-Louisiana State University General Clinical Research Center, where the human trials were conducted, was able to cover the cost of inpatient stays, outpatient visits and some of the lab work. The rest was patched together with grants from the FDA, National Institutes of Health and the Centers for Disease Control and Prevention.

The next problem was finding people to participate in the study. In the end, the majority of the 110 volunteers were students from Tulane's public health school, local medical schools and Xavier University's pharmacy collegepeople with a greater-than-average awareness of malaria. Krogstad was pleased that a significant number of African students at the public health school participated in the study.

"Since we envision doing phase two in West Africa, we didn't want an entirely white and Asian study population," he said. "If there's something in the African gene pool that's going to cause difficulty, it's better to find out now and not over there."

The purpose of the phase one study, which is now winding down, was to test the safety of the drug in healthy and malaria-free subjects. Increasingly larger doses were given in a randomized trial where some subjects received AQ-13 and some chloroquine. Investigators found no significant differences between AQ-13 and chloroquine in terms of safety and side effects, though it appears that AQ-13 is metabolized more quickly.

By the end of this year, Krogstad plans to begin phase two studies in Mali. The drug will first be tried in adults who are infected with malaria but don't have symptoms. If that's successful, it will be given to adults who are sick with drug-resistant parasites. If things go well the process then will be repeated in children, who are the ultimate target of the drug.

One of the remarkable things about Krogstad's work is that he developed what may eventually prove to be the gold-standard treatment for malaria without any input from the pharmaceutical industry. But Krogstad is getting used to the lack of interest.

"If this drug did anything for cancer, high blood pressure or heart disease, I would have a hard time fighting off the people who wanted to give me a Rolls Royce," Krogstad said.

Heather Heilman may be reached at hheilma@tulane.edu.

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